Homeostasis Lecture, 2017

MEDICAL
PHYSIOLOGY
Dr. Masika
HOMEOSTASIS
MAY,2018
DEPARTMENT OF MEDICAL PHYSIOLOGY
© 2012 Pearson Education, Inc.

References
1. Human Physiology, 6th ed. Berne & Levy

2. Review of Medical Physiology, 25th ed. Ganong, 2015
3. Textbook of Medical Physiology, 2ND Edition, Boron,
2012
4. Physiology, 5th Ed. Linda S. Costanzo
5. Widmaier, EP, Raff H, Strang KT. (2014). Vander’s
Human Physiology: The Mechanisms of body
function, 13th Edition. The McGraw-Hill Companies,
Inc., 1221 Avenue of the Americas, New York, NY.
6. TEXTBOOK OF MEDICAL PHYSIOLOGY ,
GUYTON 13TH EDITION
Course outline:
• Homeostasis
• Cell biology and genetics
• Transport processes across the cell membrane
• Mechanisms underlying mitotic cell division
• Principles of inheritance at the molecular and cellular level
• Describe the ionic basis of generation and transmission of APs
• cellular and molecular basis for normal and abnormal
neuromuscular function.
• Describe the structural and functional classifications of the
nervous system
• Describe the structure and function of the various smooth
muscle types
• Describe the structure and function of skeletal muscle type.
• Describe the structure and function of cardiac muscle type.
INTRODUCTION
• Physiology: Is the study of biological function of
how the body works, from molecular mechanisms
within cells to the actions of tissues, organs, and
systems, and how the organism as a whole
accomplishes particular tasks essential for life.

The goal of physiology
1. To explain the physical and chemical factors that are
responsible for the origin, development, and
progression of life
2. To understand and predict the body’s responses to
stimuli and to understand how the body maintains
conditions within a narrow range of values in a
constantly changing environment.
3. Medical physiology is concerned with how a state of
health and wellness is maintained in a person and,
therefore, it takes a global view of how the body
systems function and how they are controlled.

Levels of organization of the body
• 1. Chemical level
• 2. Cell level
• 3. Tissue level
• 4. Organ level.
• 5. Organ system level
• 6. Organism level

Basic cell functions
1. Obtaining food (nutrients) and oxygen (O2) from the
environment surrounding the cell.
2. Performing chemical reactions that use nutrients and
O2 to provide energy for the cells, as follows: Food +
O2 = CO2 + H2O + energy
3. Eliminating to the cell’s surrounding environment
carbon dioxide (CO2) and other by products, or
wastes, produced during these chemical reactions.
4. Synthesizing proteins and other components needed
for cell structure, for growth, and for carrying out
particular cell functions.
5. Controlling to a large extent the exchange of materials
between the cell and its surrounding environment.
Basic cell functions cont’
6. Moving materials internally from one part of the cell to
another, with some cells also being able to move
themselves through their surrounding environment.
7. Being sensitive and responsive to changes in the
surrounding environment.
8. In the case of most cells, reproducing. Some body
cells, most notably nerve cells and muscle cells lose
the ability to reproduce soon after they are formed.
This is the reason why strokes, which result in lost
nerve cells in the brain, and heart attacks, which bring
about death of heart muscle cells, can be so
devastating.

HOMEOSTASIS
• It is the maintenance by the highly coordinated,
regulated actions of the body systems of relatively
stable chemical and physical condition in the internal
fluid environment that bathes the body’s cells.
• It is not a rigid, fixed state but a dynamic steady state
in which the changes that do occur are minimized by
compensatory physiological responses.
• The term dynamic refers to the fact that each
homeostatically regulated factor is marked by
continuous change, whereas steady state implies that
these changes do not deviate far from a constant, or
steady, level.

HOMEOSTASIS CONT’
• Homeostasis is a dynamic steady state of the
constituents in the internal fluid environment that
surrounds and exchanges materials with the cells.
• As long as conditions are maintained within the normal
physiological range within the internal environment,
the cells of the body continue to live and function
properly.
• The concept of homeostasis forms basis of physiology
because it explains why various physiological
functions are to be maintained within a normal range
and in case if any function deviates from this range
how it is brought back to normal.

HOMEOSTASIS CONT’
• Understanding the concept of homeostasis also forms
the basis for clinical diagnostic procedures.
• E.g., increased body temperature beyond normal
range as in the case of fever, indicates that something
is wrong in the heat production-heat loss mechanism
in the body.
• It induces the physician to go through the diagnostic
proceedings and decide about the treatment.
• Failure to maintain homeostasis leads to illness or
death.

A homeostatic control system
• is a functionally interconnected network of body
components that operate to maintain a given factor in
the internal environment relatively constant around an
optimal level. To maintain homeostasis, the control
system must be able to:
• detect deviations from normal in the internal
environmental factor that needs to be held within
narrow limits
• integrate this information with any other relevant
information
• Make appropriate adjustments in the activity of the
body parts responsible for restoring this factor to its
desired value.
A feedback system
• Is a cycle of events in which the status of a body
condition is monitored, evaluated, changed,
remonitored, and reevaluated, and so on.
• Each monitored variable, such as body temperature,
blood pressure, or blood glucose level, is termed a
controlled condition.
• Any disruption that changes a controlled condition is
called a stimulus.
• A feedback system includes three basic components:
a receptor, a control center, and an effector.

Components of a homeostatic system
1. Regulated variable is a variable to be maintained
within a narrow normal range
2. Set point is the desired value for the regulated
variable
3. Sensors assess current status of the regulated
variable
4. Feedback controller compares current conditions with
the set point
5. Effector brings current status of regulated variable into
line with the set point

A receptor
• is a body structure that monitors changes in a
controlled condition and sends input to a control
center.
• This pathway is called an afferent pathway
(Sensory), since the information flows toward the
control center.
• Typically, the input is in the form of nerve impulses or
chemical signals.
• E.g., certain nerve endings in the skin sense
temperature and can detect changes, such as a
dramatic drop in temperature.

A control center
• In the body, for example, the brain, sets the range of
values within which a controlled condition should be
maintained (set point), evaluates the input it receives
from receptors, and generates output commands
when they are needed.
• Output from the control center typically occurs as
nerve impulses, or hormones or other chemical
signals. This pathway is called an efferent pathway
(Motor), since the information flows away from the
control center. In our skin temperature example, the
brain acts as the control center, receiving nerve
impulses from the skin receptors and generating nerve
impulses as output.
An effector
• is a body structure that receives output from the
control center and produces a response or effect that
changes the controlled condition. Nearly every organ
or tissue in the body can behave as an effector. When
your body temperature drops sharply, your brain
(control center) sends nerve impulses.
• NOTE: In a feed-back system, the response of the
system “feeds back” information to change the
controlled condition in some way, either negating it
(negative feedback) or enhancing it (positive
feedback).

Characteristics of homeostasis
1. Effectors may have opposing actions
2. Negative feedback is the process that prevents
change
3. Positive feedback is the process that perpetuates
change
4. Feedforward control is outside stimuli that alter the
normal feedback
5. Adaptive control is a form of delayed negative
feedback control that favors survival in specific
environments.

FACTORS HOMEOSTATICALLY REGULATED
1. Concentration of nutrients. Cells need a constant supply of
nutrient molecules for energy production. Energy, in turn, is
needed to support life-sustaining and specialized cell activities.
2. Concentration of O2 and CO2. Cells need O2 to carry out
energy-yielding chemical reactions. The CO2 produced during
these reactions must be removed so that acid-forming CO2
does not increase the acidity of the internal environment.
3. Concentration of waste products. Some chemical reactions
produce end products that have a toxic effect on the body’s
cells if these wastes are allowed to accumulate.
4. pH. Changes in the pH (relative amount of acid) of the ECF
adversely affect nerve cell function and wreak havoc with the
enzyme activity of all cells.

FACTORS HOMEOSTATICALLY REGULATED CONT’
• Concentration of water, salt, and other electrolytes. Because
the relative concentrations of salt (NaCl) and water in the ECF
influence how much water enters or leaves the cells, these
concentrations are carefully regulated to maintain the proper
volume of the cells. Cells do not function normally when they are
swollen or shrunken. Other electrolytes (chemicals that form ions
in solution and conduct electricity) perform a variety of vital
functions. E.g, the rhythmic beating of the heart depends on a
relatively constant concentration of potassium (K +) in the ECF.
• Blood Volume and Pressure. The circulating component of the
internal environment, the plasma, must be maintained at adequate
volume and BP to ensure body wide distribution of this important
link between the external environment and the cells.
• Temperature. Body cells function best within a narrow
temperature range. If cells are too cold, their functions slow down
too much; if they get too hot, their structural and enzymatic
proteins are impaired or destroyed.
Questions to asked about any homeostatic
response
1. What is the variable (E.g., plasma potassium
concentration, body temperature, blood glucose, blood
pressure, etc. ) that is maintained within a normal range
in the face of changing conditions?
2. Where are the receptors that detect changes in the state
of this variable?
3. Where is the integrating center to which these receptors
send information and from which information is send out
to the effectors, and what is the nature of these afferent
and efferent pathways?
4. What are the effectors, and how do they alter their
activities so as to maintain the regulated variable near
the set point of the system?
Important generalizations about homeostatic control systems
1. Stability of an internal environmental variable is
achieved by balancing inputs and outputs. It is not the
absolute magnitudes of the inputs and outputs that
matter, but the balance between them
2. In negative feedback, a change in the variable being
regulated brings about responses that tend to move
the variable in the direction opposite the original
change-that is, back toward the initial value (set point)
3. Homeostatic control systems cannot maintain
complete constancy of any given feature of the
internal environment. Therefore any regulated variable
will have a more or less narrow range of normal
values depending on the external environmental
conditions.
Important generalizations about homeostatic
control systems cont’
4. The set point of some variables regulated by
homeostatic control systems can be reset-that is
physiologically raised or lowered.
5. It is not always possible for homeostatic control
systems to maintain every variable within a narrow
normal range in response to an environmental
challenge. There is a hierarchy of importance, so that
certain variables may be altered markedly to maintain
others within their normal range

CONTRIBUTIONS OF THE BODY SYSTEMS TO
HOMEOSTASIS
The 11 body systems contribute to homeostasis in the following
important ways:
1. The circulatory system (heart, blood vessels, and blood)
transports materials such as nutrients, O2, CO2, wastes,
electrolytes, and hormones from one part of the body to
another.
2. The digestive system (mouth, esophagus, stomach,
intestines, and related organs) breaks down dietary food into
small nutrient molecules that can be absorbed into the plasma
for distribution to the body cells. It also transfers water and
electrolytes from the external environment into the internal
environment. It eliminates undigested food residues to the
external environment in the feces.

HOMEOSTASIS CONT’
3. The respiratory system (lungs and major airways) gets O2 from
and eliminates CO2 to the external environment. By adjusting the
rate of removal of acid-forming CO2, the respiratory system is also
important in maintaining the proper pH of the internal environment.
4. The urinary system (kidneys and associated “plumbing”)
removes excess water, salt, acid, and other electrolytes from the
plasma and eliminates them in the urine, along with waste
products other than CO2.
5. The skeletal system (bones, joints) provides support and
protection for the soft tissues and organs. It also serves as a
storage reservoir for calcium (Ca2+), an electrolyte whose plasma
concentration must be maintained within very narrow limits.
Together with the muscular system, the skeletal system also
enables movement of the body and its parts. Furthermore, the
bone marrow—the soft interior portion of some types of bone— is
the ultimate source of all blood cells.
HOMEOSTASIS CONT’
6. The muscular system (skeletal muscles) moves the
bones to which the skeletal muscles are attached.
From a purely homeostatic view, this system enables
an individual to move toward food or away from
harm. Furthermore, the heat generated by muscle
contraction is important in temperature regulation. In
addition, because skeletal muscles are under
voluntary control, a person can use them to
accomplish myriad other movements of his or her
own choice. These movements, which range from the
fine motor skills required for delicate needlework to
the powerful movements involved in weight lifting, are
not necessarily directed toward maintaining
homeostasis. © 2012 Pearson Education, Inc.
HOMEOSTASIS CONT’
7. The integumentary system (skin and related
structures) serves as an outer protective barrier that
prevents internal fluid from being lost from the body
and foreign microorganisms from entering.
This system is also important in regulating body
temperature.
The amount of heat lost from the body surface to the
external environment can be adjusted by controlling
sweat production and by regulating the flow of warm
blood through the skin.

HOMEOSTASIS CONT’
8. The immune system (white blood cells, lymphoid organs)
defends against foreign invaders such as bacteria and
viruses and against body cells that have become
cancerous. It also paves the way for repairing or replacing
injured or worn-out cells.
9. The nervous system (brain, spinal cord, nerves, and
sense organs) is one of the body’s two major regulatory
systems. In general, it controls and coordinates bodily
activities that require swift responses. It is especially
important in detecting changes in the external environment
and initiating reactions to them. Furthermore, it is
responsible for higher functions that are not entirely
directed toward maintaining homeostasis, such as
consciousness, memory, and creativity.
HOMEOSTASIS CONT’
10. The endocrine system (all hormone-secreting
glands) is the other major regulatory system. In
contrast to the nervous system, the endocrine system
in general regulates activities that require duration
rather than speed, such as growth. It is especially
important in controlling the concentration of nutrients
and, by adjusting kidney function, controlling the
volume and electrolyte composition of the ECF.
11. The reproductive system (male and female gonads
and related organs) is not essential for homeostasis
and therefore is not essential for survival of the
individual. It is essential, however, for perpetuating the
species.
Negative Feedback Nature of Most Control Systems
• Negative feedback is the initiation of responses that
counter deviations of a controlled variable from its normal
range and is the major control process used to maintain a
stable internal environment. A negative feedback control
system contains the following elements:
1. A set point value, which is at the center of the normal
range and is treated by the control system as the target
value.
2. Sensors that continuously monitor the controlled variable.
3. A comparator, which interprets input from the sensors to
determine when deviations from the set point have
occurred. The comparator initiates a counter response.
4. Effectors are the mechanisms that restore the set point to
its normal level.
Example of negative feedback
• A negative feedback system reverses a change in a
controlled condition. Consider the regulation of blood
pressure. Blood pressure (BP) is the force exerted by
blood as it presses against the walls of blood vessels.
1. If some internal or external stimulus causes blood
pressure (controlled variable) to rise, the following
sequence of events occurs.
2. Baroreceptors (the receptors), pressure-sensitive nerve
cells located in the walls of great blood vessels (carotid
sinus and aortic arch), detect the higher pressure.
3. The baroreceptors generate and send nerve impulses
(input) to the medulla oblongata of the brain (control
center), which interprets the impulses

Example of negative feedback cont’
4. The control center compares the value of the variable against the
set point. The control center then responds by sending nerve
impulses (output) to the heart and blood vessels (the effectors).
5. HR decreases and blood vessels dilate (widen), which cause BP to
decrease (response). This sequence of events quickly returns the
controlled condition—BP—to normal and homeostasis is restored.
Notice that the activity of the effector causes BP to drop, a result
that negates the original stimulus (an increase in BP). This is why it
is called a negative feedback system.
6. If BP increases slightly, receptors detect that change and send the
information to the control center in the brain. The control center
causes the HR to decrease, lowering BP. If BP goes down slightly,
the receptors inform the control center, which elevates the heart
rate, thereby producing an increase in BP. As a result, BP
constantly rises and falls within a normal range of values.

Positive feedback
• In positive feedback loop, the response reinforces the stimulus
rather than decreasing or removing it.
• In positive feedback, the response sends the variable being
regulated even farther from its normal value triggering a vicious
cycle of ever-increasing response and sending the system
temporarily out of control.
• Because positive feedback escalates the response, this type of
feedback requires some intervention or event outside the loop
to stop the response.
• Positive-feedback mechanisms occur when a response to the
original stimulus results in the deviation from the set point
becoming even greater. The control center provides commands
to an effector which produces a physiological response that
reinforces the initial change in the controlled condition. The
action of a positive feedback system continues until it is
interrupted by some mechanism (needs a cut-off).
Positive feedback cont’
• Unlike a negative feedback system, a positive
feedback system tends to strengthen or reinforce a
change in one of the body’s controlled conditions.
Some physiological responses use positive
feedback, causing rapid amplification.
• NOTE: In each case in which positive feedback is
useful, the positive feedback itself is part of an overall
negative feedback process. For example, in the case
of blood clotting, the positive feedback clotting
process is a negative feedback process for
maintenance of normal blood volume. Also, the
positive feedback that causes nerve signals allows the
nerves to participate in thousands of negative
feedback nervous control systems.
Explain why positive feedback would be disastrous
• If a disturbance increases the value of the controlled
variable, in a positive feedback system the controller
will respond to the disturbance by increasing the value
of the controlled variable still further. Now the
feedback signal gets still stronger resulting in a still
stronger response. Thus the control system actually
increases the rate at which the disturbance would
produce its effect and also increases the magnitude of
the effect. E.g., if a person is exposed to heat, a small
rise in body temperature, in a positive feedback
system, would raise the temperature still further, giving
rise to fever which will keep rising higher and higher.
However, there are some situations in the body which
operate on the basis of positive feedback.
Some examples where positive feedback is normal
1. Sex hormones normally inhibit gonadotropin secretion by
negative feedback. But one or two days before ovulation,
high estrogen levels actually increase the levels of
luteinizing hormone (LH) and follicle stimulating hormone
(FSH). The LH and FSH surge are essential for ovulation.
2. During labor, uterine contractions push the fetus down
towards the cervix. Stretching of the cervix stimulates
uterine contraction by positive feedback. Uterine
contractions push the fetus further down, stretching the
cervix still more, which in turn induces more uterine
contractions. Thus by positive feedback the uterine
contractions keep getting stronger till the baby is delivered.
The cycle of stretching, hormone release, and ever-
stronger contractions is interrupted only by the birth of the
baby. Then, stretching of the cervix ceases and oxytocin is
Some examples where positive feedback is normal cont’
3. Some blood coagulation reactions are autocatalytic

in nature. Once a small amount of thrombin is
formed, it acts on prothrombin to form still more
thrombin. Thus thrombin triggers the formation of still
more thrombin. Autocatalytic reactions are thus a
form of positive feedback.

• Under normal conditions, the heart pumps blood under
sufficient pressure to body cells to provide them with
oxygen and nutrients to maintain homeostasis. Upon
severe blood loss, blood pressure drops and body
cells (including heart cells) receive less oxygen and
function less efficiently. If the blood loss continues,
heart cells become weaker, the pumping action of the
heart decreases further, and blood pressure continues
to fall. This is an example of a positive feedback cycle
that has serious consequences and may even lead to
death if there is no medical intervention.

• During generation of nerve signals when the membrane
of a nerve fiber is stimulated, there is a slight leakage of
sodium ions through sodium channels in the nerve
membrane to the fiber's interior. The sodium ions
entering the fiber then change the membrane potential,
which in turn causes more opening of channels, more
change of potential, still more opening of channels, and
so forth. Thus, a slight leak becomes an explosion of
sodium entering the interior of the nerve fiber, which
creates the nerve action potential. This action potential
in turn causes electrical current to flow along both the
outside and the inside of the fiber and initiates additional
action potentials. This process continues again and
again until the nerve signal goes all the way to the end
of the fiber.
Feedforward mechanisms
• Feedforward regulation anticipates changes in regulated
variables such as internal body temperature or energy
availability, improves the speed of the body’s homeostatic
responses and minimizes fluctuations in the level of the variable
being regulated- that is, it reduces the amount of deviation from
the set point.
• Feedforward control utilizes a set of external or internal
environmental detectors. Many examples of feedforward control
are the result of learning.
• The first times they occur, early in life, perturbations in the
external environment probably cause large changes in
regulated internal environmental factors, and in responding to
these changes the CNS learns to anticipate them and resist
them more effectively. E.g., increase in heart rate that occurs in
an athlete just before a competition begins.

Feedforward mechanisms cont’
• An easily understood physiological example of
feedforward control is the salivation reflex.
• The sight, smell, or even the thought of food is enough
to start our mouths watering in expectation of the food
to eat.
• This reflex extends even further, because the same
stimuli can start the secretion of hydrochloric acid as
the stomach anticipates food on the way.
• One of the most complex feedforward reflexes
appears to be the body’s response to exercise.

Adaptive Control
• Some movements of the body occur so rapidly that there
is not enough time for nerve signals to travel from the
peripheral parts of the body all the way to the brain and
then back to the periphery again to control the movement.
• Therefore, the brain uses a principle called feed-forward
control to cause required muscle contractions. That is,
sensory nerve signals from the moving parts apprise the
brain whether the movement is performed correctly.
• If not, the brain corrects the feed-forward signals that it
sends to the muscles the next time the movement is
required. Then, if still further correction is necessary, this
will be done again for subsequent movements. This is
called adaptive control. Adaptive control, in a sense, is
delayed negative feedback.
CELL ADAPTATION
• Cell adaptation refers to the changes taking place in a
cell in response to environmental changes.
• Normal functioning of the cell is always threatened by
various factors such as stress, chemical agents,
diseases and environmental hazards.
• Yet, the cell survives and continues the function by
means of adaptation.
• Only during extreme conditions, the cell fails to
withstand the hazardous factors which results in
destruction and death of the cell.

CELL ADAPTATION CONT’
• Cellular adaptation occurs by any of the

following mechanisms.
1. Atrophy
2. Hypertrophy
3. Hyperplasia
4. Dysplasia
5. Metaplasia.

ATROPHY
• Atrophy means decrease in size of a cell. Atrophy of
more number of cells results in decreased size or
wasting of the concerned tissue, organ or part of the
body.
• Causes of Atrophy
Atrophy is due to one or more number of causes such
as:
1. Poor nourishment
2. Decreased blood supply
3. Lack of workload or exercise
4. Loss of control by nerves or hormones
5. Intrinsic disease of the tissue or organ.
Types of Atrophy
• Atrophy is of two types, physiological atrophy and
pathological atrophy.
• Examples of physiological atrophy are the atrophy of
thymus in childhood and tonsils in adolescence.
• The pathological atrophy is common in skeletal
muscle, cardiac muscle, sex organs and brain.

HYPERTROPHY
• 1. Physiological Hypertrophy
• Physiological hypertrophy is the increase in size due
to increased workload or exercise. The common
physiological hypertrophy includes:
i. Muscular hypertrophy: Increase in bulk of skeletal
muscles that occurs in response to strength training
exercise
ii. Ventricular hypertrophy: Increase in size of
ventricular muscles of the heart which is
advantageous only if it occurs in response to exercise.

2. Pathological Hypertrophy
• Increase in cell size in response to pathological
changes is called pathological hypertrophy.
• Example is the ventricular hypertrophy that occurs due
to pathological conditions such as high blood
pressure, where the workload of ventricles increases.

3. Compensatory Hypertrophy
• Compensatory hypertrophy is the increase in size
of the cells of an organ that occurs in order to
compensate the loss or dysfunction of another
organ of same type.
• Examples are the hypertrophy of one kidney when
the other kidney stops functioning; and the
increase in muscular strength of an arm when the
other arm is dysfunctional or lost.

HYPERPLASIA
• Hyperplasia is the increase in number of cells due
to increased cell division (mitosis). It is also defied
as abnormal or unusual proliferation (multiplication)
of cells due to constant cell division. Hyperplasia
results in gross enlargement of the organ.
Hyperplasia involves constant cell division of the
normal cells only. Hyperplasia is of three types.

1. Physiological Hyperplasia
• Physiological hyperplasia is the momentary
adaptive response to routine physiological
changes in the body.
• For example, during the proliferative phase of
each menstrual cycle, the endometrial cells in
uterus increase in number.

2. Compensatory Hyperplasia
• Compensatory hyperplasia is the increase in number
of cells in order to replace the damaged cells of an
organ or the cells removed from the organ.
• Compensatory hyperplasia helps the tissues and
organs in regeneration. It is common in liver.
• After the surgical removal of the damaged part of liver,
there is increase in the number of liver cells resulting
in regeneration. Compensatory hyperplasia is also
common in epithelial cells of intestine and epidermis.

3. Pathological Hyperplasia
• Pathological hyperplasia is the increase in number
of cells due to abnormal increase in hormone
secretion. It is also called hormonal hyperplasia.
• For example, in gigantism, hypersecretion of
growth hormone induces hyperplasia that results in
overgrowth of the body

DYSPLASIA
• Dysplasia is the condition characterized by

the abnormal change in size, shape and
organization of the cell. Dysplasia is not
considered as true adaptation and it is
suggested as related to hyperplasia. It is
common in epithelial cells of cervix and
respiratory tract.

METAPLASIA
• Metaplasia is the condition that involves
replacement of one type of cell with another type of
cell. It is of two types.
• 1. Physiological Metaplasia
• Replacement of cells in normal conditions is called
physiological metaplasia. Examples are
transformation of cartilage into bone and
transformation of monocytes into macrophages.

2. Pathological Metaplasia
• Pathological metaplasia is the irreversible replacement
of cells due to constant exposure to harmful stimuli.
For example, chronic smoking results in
transformation of normal mucus secreting ciliated
columnar epithelial cells into non-ciliated squamous
epithelial cells, which are incapable of secreting
mucus. These transformed cells may become
cancerous cells if the stimulus (smoking) is prolonged.

THE INTERNAL ENVIRONMENT
• The goal of homeostasis is to provide an optimal fluid
environment for cellular function. The body fluids are
divided into two major functional compartments.
• 1. The fluid inside cells, taken collectively, is the
intracellular fluid (ICF) compartment.
• 2. The fluid outside cells is the extracellular fluid (ECF)
compartment, which is subdivided into the interstitial
fluid and the blood plasma.
• The concept of an internal environment in the body
correlates with the interstitial fluid bathing cells. There is
free exchange of water and small solutes in the ECF
between IF and plasma across the blood capillaries. In
contrast, the exchange of most substances between IF
and ICF is highly regulated and occurs across plasma
cell membranes. © 2012 Pearson Education, Inc.
THE INTERNAL ENVIRONMENT CONT’
• The volume of total body water is approximately 60%
of body weight in men and 50% in women.
• About 60% of total body water is ICF and 40% is ECF.
• Approximately 80% of ECF is interstitial fluid and the
remaining 20% is blood plasma, which is contained
inside the vascular system.
• ECF is high in NaCl and low in K+, whereas ICF is
high in K+ and low in NaCl.
• Interstitial fluid is similar in composition to plasma,
except that interstitial fluid has almost no protein.
• Osmolarity is the same in all compartments.

internal environment cont’
• This environment surrounding each cell is called
internal environment. It is part of extracellular fluid.
• It is from this fluid the cells receive oxygen and
nutrients and cells excrete their waste into it.
• But the interstitial fluid is small quantity so that:
• i. Nutrients in it must be replenished.
• ii. Waste products should be removed continuously
and promptly otherwise its pH will change, and its
composition does not remain suitable for optimal
functioning of the cell.

BODY FLUIDS CONT’
• In normal 70 kg adult human (Physiological man) the
total body water averages about 60% of the body
weight (= 42 liters). Percentage can change
depending on— (a) age (b) sex, and (c) degree of
obesity, because total body water depends on fat
content. Total body fluid is distributed among two
major compartments:
• Extracellular fluid (ECF): Fluid outside the cell (1/3 of
total body water).
• Intracellular fluid (ICF): Fluid inside the cell (2/3 of total
body water).

Differences between Extracellular and
Intracellular Fluids
• The extracellular fluid contains large amounts of
sodium, chloride, and bicarbonate ions plus
nutrients for the cells, such as oxygen, glucose,
fatty acids, and amino acids.
• It also contains carbon dioxide that is being
transported from the cells to the lungs to be excreted,
plus other cellular waste products that are being
transported to the kidneys for excretion.

Differences between Extracellular and
Intracellular Fluids
• The intracellular fluid differs significantly from the
extracellular fluid; for example, it contains large
amounts of potassium, magnesium, and phosphate
ions instead of the sodium and chloride ions found in
the extracellular fluid.
• Special mechanisms for transporting ions through the
cell membranes maintain the ion concentration
differences between the extracellular and intracellular
fluids.

Blood Volume
• Blood contains both extracellular fluid (the fluid in
plasma) and intracellular fluid (the fluid in the red
blood cells). Blood is plasma with cells suspended in
it. They are: (i) RBC, (ii) WBC, (iii) platelets. Blood is
present in separate fluid compartments of its own.
Therefore, considered as separate fluid compartment.
It contains ECF and ICF both. Average blood volume
of normal adult is about 7 percent of body weight, or
about 5 liters. Out of which 55-60% is plasma and 40-
45% is blood cells. Volume occupied by blood cells is
known as packed cell volume or hematocrit. It is
determined by centrifuging blood in a hematocrit tube
until the blood cells become tightly packed in the
bottom. © 2012 Pearson Education, Inc.
Hematocrit (Packed Red Cell Volume)
• The hematocrit is the fraction of the blood composed of
red blood cells, as determined by centrifuging blood in a
"hematocrit tube" until the cells become tightly packed in
the bottom of the tube. It is impossible to completely pack
the red cells together; therefore, about 3 to 4 percent of
the plasma remains entrapped among the cells, and the
true hematocrit is only about 96 percent of the measured
hematocrit. In men, the measured hematocrit is normally
about 0.40, and in women, it is about 0.36. In severe
anemia, the hematocrit may fall as low as 0.10, a value
that is barely sufficient to sustain life. Conversely, there are
some conditions in which there is excessive production of
red blood cells, resulting in polycythemia. In these
conditions, the hematocrit can rise to 0.65.
1. Explain why the effects of positive feedback
would be disastrous
• Answer: If a disturbance increases the value of the
controlled variable, in a positive feedback system the
controller will respond to the disturbance by increasing
the value of the controlled variable still further. Now
the feedback signal gets still stronger resulting in a still
stronger response. Thus the control system actually
increases the rate at which the disturbance would
produce its effect and also increases the magnitude of
the effect. For example, if a person is exposed to heat,
a small rise in body temperature, in a positive
feedback system, would raise the temperature still
further, giving rise to fever which will keep rising higher
and higher.
2. What is feedforward control?
• Answer: It is the same as anticipatory

control. It is so called because it depends on
being fed information that does not still exist.
In other words, it operates on the basis of
information that is forward in time.

3. If we have homeostatic mechanisms for regulating
blood pressure, why do some people get hypertension?
• Answer: For regulation of blood pressure, there are
short-term as well as long-term homeostatic
mechanisms. Hypertension represents the failure of
long-term mechanisms. There are also reports of
reduced sensitivity of baroreceptors, a short-term
mechanism, in hypertensive patients. But this
reduction may be an effect rather than the cause of
the hypertension. Sustained hypertension possibly
leads to an adaptation of baroreceptors, which
manifests as reduced sensitivity (in the same way as
staying in a stinking area for some time leads to
reduced sensitivity to the smell).
4. Can a single effector work in both directions:
stepping up, or stepping down, a function?
• Answer: Yes, it can. For example, if increased activity of a
nerve increases the heart rate, decreased activity of the
same nerve will decrease the heart rate. Of course, this is
possible only if there is some basal activity in the nerve all
the time. But having two effectors makes the control
system more efficient. For example, the body has two sets
of nerves for regulation of heart rate: sympathetic and
parasympathetic. Sympathetic activity increases the heart
rate while parasympathetic activity decreases the heart
rate. The two together act like the accelerator and brake in
a car. Although a car can be slowed down by using only
the accelerator, even the best driver sometimes has to use
the brake to make slowing down more efficient in order to
avoid an accident.
5. Why is extracellular fluid referred to as the
body’s internal environment?
• Answer: Most of the body’s cells are not able to exchange
materials directly with the external environment because they
are not in direct contact with it. Instead, cells receive oxygen
and nutrients from the bloodstream, which also carries carbon
dioxide and waste products away from cells. Moreover, most
cells are not in direct contact with the blood, but instead are
surrounded by a separate fluid that exchanges materials with
the blood. Because this fluid constitutes the immediate
environment of most of the body’s cells, it is called the internal
environment. Internal environment in the body is the
extracellular fluid (ECF) in which the cells live. It is the fluid
outside the cell and it constantly moves throughout the body. It
includes blood, which circulates in the vascular system and fluid
present in between the cells called interstitial fluid. ECF
contains nutrients, ions and all other substances necessary for
the survival of the cells.© 2012 Pearson Education, Inc.
6. By giving a suitable example, explain why sometimes
in homeostasis variables do not remain within the same
narrow range of values at all times.
• Answer: Although homeostasis is the maintenance of a normal
range of values, this does not mean that all variables remain
within the same narrow range of values at all times. Sometimes
a deviation from the usual range of values can be beneficial.
For example, during exercise the normal range for blood
pressure differs from the range under resting conditions and the
blood pressure is significantly elevated. Muscle cells require
increased oxygen and nutrients and increased removal of
waste products to support their heightened level of activity
during exercise. Elevated blood pressure increases delivery of
blood to muscles during exercise, thereby increasing the
delivery of oxygen and nutrients and the removal of waste
products—ultimately maintaining muscle cell homeostasis.

Types of Chemical
Signaling
Chemical signaling between
cells is one of the most
important ways that activities
of tissues and organs are
.coordinated
The nervous system is the
other major coordinating
system in animals, but even
here chemical signaling is
used between adjacent
.neurons

Modes of cell-cell signaling
1. Direct cell-cell or cell-matrix
2. Indirect: Secreted molecules.
A. Endocrine signaling. The signaling molecules are hormones
secreted by endocrine cells and carried through the circulation
system to act on target cells at distant body sites.
B. Paracrine signaling. The signaling molecules released by one
cell act on neighboring target cells (neurotransmitters).
C. Autocrine signaling. Cells respond to signaling molecules that

they themselves produce (response of the immune system to
foreign antigens, and cancer cells).

Intercellular signaling
Intercellular signaling can occur over long
distances (endocrine) or short distances.
hormone
neurotransmitter
some cytokines
some growth
factors

Different Types of Chemical Signals
Can Be Received by Cells
• Signaling molecules are often classified based on
the distance between the site of production and
the target
– Endocrine signals are produced far from the target
tissues, which they reach via the circulatory system
– Paracrine signals are diffusible and act over a
short range

Types of signals
• Classification of signaling molecules

– Juxtacrine signals require physical
contact between sending and receiving
cells
– Autocrine signals act on the same cell
that produces them

Local and Long-Distance Signaling
• Cells in a multicellular organisms communicate by
chemical messengers
• Animal and plant cells have cell junctions that
directly connect the cytoplasm of adjacent cells
• In local signaling, animal cells may communicate
by direct contact
• In many other cases, animal cells communicate
using local regulators, messenger molecules that
travel only short distances
• In long-distance signaling, plants and animals use
chemicals called hormones

Plasma membranes
Gap junctions Plasmodesmata

between animal cells between plant cells
Cell junctions
PowerPoint Lectures for

Biology, Seventh Edition
Neil Campbell and Jane Reece
Lectures byCell-cell
Chris Romero
recognition
Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings
Figure 14-1

Local signaling Long-distance signaling
Target cell Electrical signal Endocrine cell Blood

along nerve cell vessel
triggers release of
neurotransmitter
Neurotransmitter
Secreting Secretory diffuses across
cell vesicle synapse Hormone travels
in bloodstream
to target cells
Local regulator
diffuses through Target cell Target
extracellular fluid is stimulated cell
Paracrine signaling Synaptic signaling

Biology, Seventh Edition Hormonal signaling
Lectures by Chris Romero

Ligands and receptors
• When a messenger reaches its target, it binds to

receptors on the surface of the target cell
• A messenger that binds a target receptor is called
a ligand; it may bind a receptor on the surface or
inside the target cell
• In either case, the ligand is the “primary
messenger”

Small Molecules and Ions as Second
Messengers
• Second messengers are small, nonprotein, water-
soluble molecules or ions
• The extracellular signal molecule that binds to the
membrane is a pathway’s “first messenger”
• Second messengers can readily spread
throughout cells by diffusion
• Second messengers participate in pathways
initiated by G-protein-linked receptors and
receptor tyrosine kinases

Second messengers
• Ligand binding may trigger production of molecules
in the receiving cell
• These small molecules or ions that relay signals
from one location to another in the cell are called
second messengers
• A cascade of changes may be induced in the
receiving cell
• The ability of a cell to respond to ligand-receptor
binding by altering its behavior or gene expression
is called signal transduction

Figure 14-2A

Some signaling molecules
1. Steroid hormones
This class of molecules diffuse across the plasma membrane and bind to
Receptors in the cytoplasm or nucleus. They are all synthesized from
cholesterol.
They include sex steroids (estrogen, progesterone, testosterone)
corticosteroids
(glucocorticoids and mineralcorticoids)
Thyroid hormone, vitamin D3, and retinoic acid have different structure
and
function but share the same mechanism of action with the other steroids.
Steroid Receptor Superfamily. They are transcription factors that
function either
as activators or repressors of transcription.

2. Nitric oxide (NO) and Carbon Monoxide (CO)
NO, a simple gas, is able to diffuse across the membrane,
and alters the activity of intracellular target enzymes. It’s
extremely unstable, so its effects are local. Ex. It signals
the dilation of blood vessels.
3. Neurotransmitters
They signal from neuron to neuron or from neuron to
other target cell
(ex. muscle cell ).

Nuclear receptors
 Nonpolar signal
molecules can pass Steroid
through the plasma hormones
membrane.
Thyroid
hormones

Nuclear receptors
Nonpolar signal
molecules can pass
through the plasma
membrane.
Receptor can be in
cytosol or nucleus.
Hormone-receptor
complex acts in the
nucleus to affect
gene expression.

Nuclear receptors

Steroid Hormones
Steroid hormones are soluble in the plasma
membrane and readily enter the cytosol where
they bind to a mobile receptor.
The hormone-receptor complex enters the nucleus
and binds to specific genes where it acts as a
transcription factor which turns on the genes.
Messenger RNA is transcribed, leaves the
nucleus, and is translated into a specific protein
by ribosomes.
The specific proteins then carry out functions (if
they are enzymes) or produce structures in the
target cell.
Because steroid hormones initiate protein
synthesis, their effects are produced more slowly,
but are more long-lasting than those produced by
other hormones.
Problems with steroid signaling
Females who produce

excess testosterone can
have hyperandrogenism.
Caster Semenya
2009 World 800-Meter Champion
Jazz singer Individuals who have a

Eden Atwood defective testosterone
X,Y Genotype receptor have androgen
insensitivity.
Anabolic Steroids
 Anabolic steroids are

testosterone agonists
used to build skeletal
muscle and stimulate
bone growth.
 Their use in sports was

pioneered by East
Germany, which had a
systematic
governmental doping
program from 1965 to
1990.

Anabolic Steroids
At the first world swimming
championships, in 1973, East
German women won 10 of the 14
gold medals available, setting eight
world records.
Three years later at the Montreal llona Slupianek

Summer Olympics, the East Shot Put World
German women won 11 of 13 Record Holder
events. 1980 –1984

Signal transduction
Feedback
Regulation
Amplification

The Three Stages of Cell Signaling: A Preview
• Earl W. Sutherland discovered how the hormone
epinephrine acts on cells
• Sutherland suggested that cells receiving signals
went through three processes:
– Reception
– Transduction
– Response

Three Steps in Cell Signaling
Target organ specificity is the result of specific receptor molecules
for the hormone, either on the plasma membrane surface, or in
some cases in the cytoplasm, of cells in the target organ.
1) Reception 2) Transduction 3) Response

1- Reception: A signal molecule binds to a
receptor protein, causing it to change shape
• The binding between a signal molecule

(ligand) and receptor is highly specific
• A conformational change in a receptor is
often the initial transduction of the signal
• Most signal receptors are plasma membrane
proteins

Intracellular Receptors
• Some receptor proteins are intracellular, found in
the cytosol or nucleus of target cells
• Small or hydrophobic chemical messengers can
readily cross the membrane and activate receptors
• Examples of hydrophobic messengers are the
steroid and thyroid hormones of animals
• An activated hormone-receptor complex can act as
a transcription factor, turning on specific genes

Hormone EXTRACELLULAR
(testosterone) FLUID The steroid
hormone testosterone
passes through the
plasma membrane.
Plasma
membrane Testosterone binds
Receptor to a receptor protein
protein in the cytoplasm,
Hormone- activating it.
receptor
complex
The hormone-
receptor complex
enters the nucleus
and binds to specific
genes.
DNA
mRNA The bound protein

stimulates the
PowerPoint Lectures for transcription of
the gene into mRNA.
NUCLEUS New protein
The mRNA is
translated into a
specific protein.
CYTOPLASM

Properties of signal transduction

Properties of signal transduction
 In other words, signaling

proteins can interact with
more than one target,
forming complexes with
different properties.

Interfering with chemical signals
Some molecules interfere with the normal
signaling pathway.
 Agonists bind to the

receptor and mimic
the effects of the
normal signal.
Antagonists act as
competitive
inhibitors of the
normal signal.
Receptors in the Plasma Membrane
• Most water-soluble signal molecules bind to
specific sites on receptor proteins in the
plasma membrane
• There are three main types of membrane
receptors:
– G-protein-linked receptors
– Receptor tyrosine kinases
– Ion channel receptors

Categories of receptors
• Receptors can be classified into several
basic categories
– Ligand-gated channels
– Plasma membrane receptors of two
types
• Those linked to G-proteins
• Those linked to protein kinases

Signal Transduction Mechanisms:
II. Messengers and Receptors
• In the second major means of
intercellular communication the signal is
transmitted by regulatory chemical
messengers
• Receptors are located on receiving cells
that can be quite distant from the
secreting cell

Receptor Binding Involves Specific Interactions
Between Ligands and Their Receptors
• In most cases the binding of a receptor and ligand
resembles the binding of an enzyme and its substrate
• The receptor specific for a certain ligand is called the
cognate receptor
• A receptor bound to its ligand is said to be occupied
• Messengers bind to receptors in a highly specific way,
through several noncovalent bonds
• This is achieved through
– The binding site (or binding pocket) on the receptor
that fits the messenger very closely
– The necessary amino acid side chains, positioned to
form chemical bonds with the messenger
Receptor Binding Activates a Sequence of Signal
Transduction Events Within the Cell
• When a ligand binds to its cognate receptor it either
induces a change in receptor conformation or
causes receptors to cluster
• Once this takes place, a preprogrammed sequence
of events is initiated inside the cell
• Cells can be exposed to a multitude of signals at
any given moment
• Cells must integrate these signals to produce
appropriate responses
• A single receptor can activate multiple pathways, or
multiple pathways can converge onto the same
molecules
Types of signal transducers

Figure 14-2B

Crosstalk
• Sometimes activated components from one

pathway affect components of another pathway
• This is called signaling crosstalk
• Signaling is more of a network of biochemical

pathways than a linear sequence of events

Signal Amplification
• Very small quantities of ligand are often sufficient
to elicit a response from a target cell
• At each step in the resulting cascade of events, a
signaling intermediate stimulates the production of
many molecules needed for the next step
• This multiplication of the effect of the signal is
called signal amplification
• Multistep pathways can amplify a signal: A few
molecules can produce a large cellular response
• Multistep pathways provide more opportunities for
coordination and regulation

Signal Transduction Pathways
• The molecules that relay a signal from receptor to
response are mostly proteins
• Like falling dominoes, the receptor activates
another protein, which activates another, and so
on, until the protein producing the response is
activated
• At each step, the signal is transduced into a
different form, usually a conformational change

Protein Phosphorylation and Dephosphorylation
• In many pathways, the signal is transmitted by a
cascade of protein phosphorylations
• Phosphatase enzymes remove the phosphates
• This phosphorylation (kinases) and dephosphorylation
(phosphotases) system acts as a molecular switch,
turning activities on and off
• A kinase, alternatively known as a
phosphotransferase, is a type of enzyme that
transfers phosphate groups from high-energy donor
molecules, such as ATP, to specific substrates. The
process is referred to as phosphorylation.

Signal molecule
Receptor
Activated relay
molecule
Inactive
protein kinase
1 Active
protein
kinase
1
Ph
Inactive
o
sp
protein kinase ATP
ho
2 ADP Active P
ry
la
protein
iot
kinase
n
PP
ca
Pi 2
sc
a de
Inactive
protein kinase ATP
ADP Active P
3
protein
PowerPoint Lectures for PP kinase
Pi 3
Inactive
Neil Campbell and Jane Reece protein ATP
ADP P
Active Cellular
PP protein response
Pi
Phosphorylation
Cascade
Signal transduction pathways often
involve an enzyme phosphorylation
.cascade
A series of protein kinases each
activate the next in a series by
phosphorylating the inactive
.precursor
Because each protein kinase is an
enzyme it catalyzes activation of a
number of the inactive kinases of the
.next member in the series
The result is a large amplification of
the original signal, binding of a
.hormone to the external receptor
G Protein-Linked Receptors
• The G protein-linked receptor family is so named

because ligand binding causes a change in
receptor conformation that activates a particular G
protein
• G protein: guanine-nucleotide binding protein

G Protein-Linked Receptors cont’
• A G-protein-linked receptor is a plasma membrane
receptor that works with the help of a G protein
• The G-protein acts as an on/off switch: If GDP is
bound to the G protein, the G protein is inactive
• Cells produce signals, in some cases by
displaying molecules on their surfaces or by
releasing a chemical signal
• Multicellular organisms can control the activities
of specialized cells through release of chemical
messengers

Many Seven-Membrane Spanning
Receptors Act via G Proteins
• A portion of an activated G protein binds a target
protein, altering its activity
• A class of receptors of great clinical importance is
the opioid receptors, to which narcotic drugs such
as morphine bind

G-protein coupled receptors

The Structure and Regulation of G
Protein-Linked Receptors
• G protein-linked receptors have a similar
structure but quite different amino acid
sequence
• The receptor forms seven transmembrane 
helices connected by alternating cytosolic or
extracellular loops
• The extracellular portion of each receptor
has a unique messenger-binding site
Signal-binding site
Segment that
Biology, Seventh interacts
Edition with
G Jane
Neil Campbell and proteins
Reece
Lectures by Chris Romero G-protein-linked receptor

Figure 14-4

Protein kinase A
• Protein kinase A (PKA) is activated by G protein-

mediated signaling
• PKA can phosphorylate other amino acids on the

receptor and inhibit it
• This is a good example of negative feedback during

cell signaling

G protein function
• When a messenger binds to a G protein-linked
receptor the resulting change in receptor
conformation causes a G protein to associate with
it and release its GDP
• The G then binds a new GTP molecule and

detaches from the complex
• Either the G or the G initiates signal transduction

depending on the G protein

Figure 14-5

G protein inactivation
• G proteins remain active as long as the Ga
subunit is bound to GTP and separate from the
Gbg subunit
• Once the Ga subunit has hydrolyzed GTP to
GDP, it reassociates with Gbg
• Some Ga proteins are not very efficient at GTP
hydrolysis

Cyclic AMP
• Cyclic AMP (cAMP) is one of the most widely used
second messengers. Is a Second Messenger Whose
Production Is Regulated by Some G Proteins
• cAMP is formed from cytosolic ATP by adenylyl
cyclase, an enzyme that is anchored in the plasma
membrane
• Adenylyl cyclase, an enzyme in the plasma
membrane, converts ATP to cAMP in response to an
extracellular signal
• The enzyme is inactive until bound to activated
Gsa; (by receptor-ligand stimulated acquisition of GTP
and release from Gsbg)
• Gia inhibits adenylyl© 2012
cyclase
Pearson Education, Inc.
Figure 14-7

cAMP function
• cAMP is important in many cellular events
• Its main target is protein kinase A (PKA), which it
regulates by separating the regulatory and catalytic
subunits
• PKA phosphorylates a variety of proteins on ser or
thr residues, using ATP as the source of phosphate
• N/B: Other components of cAMP pathways are G
proteins, G-protein-linked receptors, and protein
kinases
• Further regulation of cell metabolism is provided by
G-protein systems that inhibit adenylyl cyclase

First messenger
(signal molecule
such as epinephrine)
Adenylyl
G protein cyclase
G-protein-linked GTP
receptor
ATP
Second
cAMP messenger
Protein
PowerPoint Lectures for kinase A
Cellular responses
Cyclic AMP as a
Second Messenger
Most water-soluble hormones do not
readily enter the target cell - they
.bind to a surface receptor
In many cases, a G protein is activated

which then activates an enzyme, adenylyl
cyclase which converts ATP to cyclic
.AMP (cAMP)
cAMP then serves as a second messenger

which activates another enzyme in the
.cell
cAMP initiates a chain of events (the

signal transduction pathway) that results
in some specific response of the cell to the
.first messenger (hormone)
GS-protein pathway:
β-adrenergic receptor

GS-protein activation
 A “GTP Switch” protein

is active when GTP is
bound; inactive when
GDP is bound.
 When α subunit binds
GTP, it separates from
β and γ.
 Activated α subunit
finds AC and turns it on.
 Intrinsic GTPase activity

turns α subunit off- it
finds β and γ.
Activation of AC
Activated AC makes
cAMP.
One target of cAMP

is protein kinase A
(PKA).

Activation of Protein Kinase A
PKA is active
only when 4
cAMP are
bound, freeing
the two catalytic
subunits.
Active PKA has

many effects,
depending on
cell type.

Table 14-1

cAMP: second messenger

Inhibitory G proteins

Figure 11.16
Reception
Binding of epinephrine to G protein-coupled receptor (1 molecule)
Transduction
Inactive G protein
Active G protein (102 molecules)
Inactive adenylyl cyclase

Active adenylyl cyclase (10 2)
ATP
Cyclic AMP (104)
Inactive protein kinase A

Active protein kinase A (104)
Inactive phosphorylase kinase

Active phosphorylase kinase (10 5)
Inactive glycogen phosphorylase

Active glycogen phosphorylase (10 6)
Response
Glycogen
Glucose 1-phosphate
(108 molecules)

Disruption of G Protein Signaling
Causes Several Human Diseases
• Some bacteria cause their diseases through
their effects on heterotrimeric G proteins
• Cholera: when Vibrio cholerae colonizes the
gut it secretes cholera toxin; this toxin
modifies Gs so that it cannot hydrolyze GTP
• This alters secretion of salts and fluids in the
intestine and can cause death by dehydration

Toxins that Target G proteins
• Vibrio cholerae produces the cholera
toxin, which ADP-ribosylates GSα,
inhibiting GTPase activity.
Net result:
cAMP is high

G protein signaling and human diseases
• Whooping cough: Bordetella pertussis
secretes pertussis toxin that acts on Gi, so
that it can no longer inhibit adenylyl cyclase
• This causes an accumulation of fluid in the
lungs and the persistent cough associated
with the disease

Toxins that Target G proteins
• Bordetella pertussis produces the
pertussis toxin, which ADP-ribosylates
GIα, inhibiting nucleotide exchange.
GI Net result:
Pertussis toxin cAMP is high
GI
GI is kept off, so AC is on and cAMP levels increase

Drugs that Enhance cAMP
• Caffeine, theophylline, Sildenafil

(Viagra) inhibit cAMP
phosphodiesterase.
cAMP
phosphodiesterase
Net result: cAMP is high

Termination of Response
Pathway can be terminated at any step!
Removal of signal
Desensitization of
receptor
Hydrolysis of GTP
(promoted by GTPase
activator proteins
[GAPS])
Degradation of 2nd
messenger
Hydrolysis of
phosphates
Strategy #1: Mechanisms of Desensitization
Receptor Level

Mechanisms of Desensitization
Strategy #2:
Downstream Effects
Morphine
receptor works
through GI.
Body responds
to morphine by
increasing AC
and PKA
expression.

GUANYLYL CYCLASE
• cyclic guanosine monophosphate (cyclic GMP or
cGMP) is important in vision in both rod and cone
cells.
• In addition, there are cGMP-regulated ion channels,
and cGMP activates cGMP-dependent kinase,
producing a number of physiologic effects.
• Guanylyl cyclases are a family of enzymes that
catalyze the formation of cGMP.
• They exist in two forms-One form has an extracellular
amino terminal domain that is a receptor, a single
transmembrane domain, and a cytoplasmic portion
with guanylyl cyclase catalytic activity.

GUANYLYL CYCLASE CONT’
• Two are receptors for atrial natriuretic peptide (ANP),
and a third binds an Escherichia coli enterotoxin and
the gastrointestinal polypeptide guanylin.
• The other form of guanylyl cyclase is soluble, contains
heme, and is not bound to the membrane and are
activated by nitric oxide (NO) and NO-containing
compounds.
• When released fromcells, NO acts locally in a
paracrine fashion to relax the smooth muscle
component of certain blood vessels, which allows the
blood vessel to dilate, or open, more.

Nitric Oxide (NO)
• Is released with sexual stimulation from nerve endings
and endothelial cells in the spongy erectile tissue,
the corpus cavernosum of the penis.
• The enzyme guanylate cyclase then converts
guanosine triphosphate (GTP) into cyclic guanosine
monophosphate (cGMP).
• cGMP causes the smooth muscle to relax, which
causes an inflow of blood which then leads to an
erection.
• cGMP is then hydrolysed back to the inactive GMP by
phosphodiesteras type 5 (PDE5).

Nitric Oxide (NO) cont’
• The levels of cGMP are therefore controlled by the
activation of cyclic nucleotide cyclase and the
breakdown by PDE5 (acted upon by sildenafil)
• Men who suffer from erectile dysfunction often
produce too little amounts of NO.
• The small amount of cGMP they produce is broken
down at the same rate and therefore doesn't have the
time to accumulate and cause a prolonged
vasodilation effect.
• Sildenafil works by inhibiting the enzyme PDE5.
• This means that cGMP is not hydrolysed as fast and
this allows the smooth muscle to relax. Sildenafil is a
potent and highly selective inhibitor of PDE5
G-Proteins Using Inositol
Trisphosphate and Diacylglycerol as
Second Messengers
• Inositol-1,4,5-trisphosphate (IP3) functions as a
second messenger
• It is generated from PIP2 when the enzyme
phospholipase C is activated
• It cleaves PIP2 into IP3 and diacylglycerol, both of
which are second messengers in a variety of
cellular events

Table 14-2

INOSITOL TRISPHOSPHATE & DIACYLGLYCEROL
AS SECOND MESSENGERS
• The link between membrane binding of a ligand that

acts via Ca2+ and the prompt increase in the
cytoplasmic Ca2+ concentration is often IP3.
• When one of these ligands binds to its receptor,
activation of the receptor produces activation of
phospholipase C (PLC) on the inner surface of the
membrane.
• Ligands bound to GPCR can do this through the Gq
heterotrimeric G-proteins, while ligands bound to
tyrosine kinase receptors can do this through other
cell signaling pathways.

IP3 and diacylglycerol
• PLC has at least 8 isoforms; PLCβ is activated by
heterotrimeric G-proteins, while PLCγ forms are
activated through tyrosine kinase receptors.
• PLC isoforms can catalyze the hydrolysis of the
membrane lipid phosphatidylinositol 4,5-
diphosphate (PIP2) to form IP3 and DAG.
• The IP3 diffuses to the endoplasmic reticulum where it
triggers the release of Ca2+ into the cytoplasm by
binding the IP3 receptor, a ligand-gated Ca2+ channel.
• DAG is also a second messenger; it stays in the cell
membrane where it activates one of several isoforms
of protein kinase C.
Gq activates phospholipase C

DAG and IP3
IP3

Gq acts through DAG and IP3

Figure 14-9

IP3 and diacylglycerol in signaling
• A signal relayed by a signal transduction pathway
may trigger an increase in calcium in the cytosol
• A ligand binds its membrane receptor, leading to
activation of a G protein, Gq
• Gq activates a phospholipase C called Cb, generating
both IP3 and diacylglycerol
• IP3 diffuses through the cytosol and binds a ligand-
gated calcium channel, the IP3 receptor channel

EXTRACELLULAR Signal molecule
FLUID (first messenger)
G protein
DAG
GTP
G-protein-linked PIP2
receptor Phospholipase C
IP3 (second
messenger)
IP3-gated
calcium channel
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Various
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Neil (ER)
Campbell and Jane Reece activated sponses
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(second
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IP3 and diacylglycerol in signaling
• When IP3 binds the receptor, calcium is released
into the cytosol
• Calcium and diacylglycerol activate members of
the protein kinase C (PKC) family, which then
phosphorylate ser and thr residues on a variety of
target proteins

Figure 14-10

Calcium in signaling
• Ca2+ plays an essential role in regulating a variety
of cellular functions
• Calcium concentrations are maintained at low
levels through calcium ATPases in the plasma
membrane and ER; these transport calcium ions
out of the cytosol

Calcium in signaling (continued)
• Calcium concentrations can be released by

opening calcium channels in the plasma
membrane, as in neuronal signaling
• Calcium can also be released from storage in the

ER through the IP3 receptor channel
• The IP3 receptor channel and the ryanodine

receptor channels are sensitive to calcium
Figure 14-12

Calcium in signaling (continued)
• A rapid increase in calcium ions can cause the

ryanodine receptor channels to open, allowing
calcium to enter the cytoplasm from the ER
• This is termed calcium-induced calcium release

Calcium Release Following Fertilization
of Animal Eggs
• Animal sperm are activated by release of calcium
• Activated sperm then bind to the surfaces of

mature eggs and unite with them, triggering the
release of Ca2+ from internal stores
• Ca2+ release begins at the site of sperm entry

then spreads across the egg surface like a wave

Roles of calcium in fertilization
• Calcium release is necessary for two crucial events
- It stimulates vesicles called cortical granules to

release their contents and alter the properties of the
vitelline envelope (slow block to polyspermy)
- It induces egg activation, the resumption of metabolic

processes and reorganization of egg contents,
necessary for embryonic development to proceed

Figure 14-13B

Calcium Binding Activates Many
Effector Proteins
• Calcium can bind directly to effector proteins,
altering their activity
• The protein calmodulin mediates calcium-

activated processes in the cell
• Calmodulin has a structure like an arm with a

hand at each end; each binds two Ca2+

Common Mechanisms by Which Stimulation
of a Cell Leads to an Increase in Cytosolic
Ca2+ Concentration
• I. Receptor activation
A. Plasma-membrane Ca2+ channels open in response
to a first messenger; the receptor itself may contain
the channel, or the receptor may activate a G-protein
that opens the channel via a second messenger.
B. Ca2+ is released from the endoplasmic reticulum;
this is typically mediated by IP3.
C. Active Ca2+ transport out of the cell is inhibited by a
second messenger.
II. Opening of voltage-gated Ca2+ channels

Major Mechanisms by Which an Increase in
CytosolicCa2+ Concentration Induces the
Cell’s Responses
• I. Ca2+ binds to calmodulin. On binding Ca2+, the
calmodulin changes shape, which allows it to activate
or inhibit a large variety of enzymes and other
proteins. Many of these enzymes are protein kinases.
• II. Ca2+ combines with Ca2+ -binding intermediary
proteins other than calmodulin. These proteins then
act in a manner analogous to calmodulin.
• III. Ca2+ combines with and alters response proteins
directly, without the intermediation of any specific Ca 2+
-binding protein.

Protein Kinase-Associated Receptors
• Protein kinase-associated receptors are not only

receptors, but also function as kinases
• Ligand binding stimulates their kinase activities
• Signaling of these receptor protein kinases is

transmitted through a phosphorylation cascade
• Kinases are either tyrosine kinases or

serine/threonine kinases
Growth Factors Often Bind Protein
Kinase-Associated Receptors
• For cells to divide they need enough nutrients for
growth and signals to stimulate cell growth
• Cultured cells in vitro will not grow, even with

enough nutrients, unless blood serum is provided
• Messengers in the serum that stimulate growth are

called growth factors

Platelet-derived growth factor
• The growth factors secreted by platelets stimulate

fibroblasts to form new connective tissue
• The serum that remains after clotting contains

large amounts of platelet-derived growth factor
(PDGF)
• The receptor for PDGF is a receptor tyrosine

kinase
Receptor tyrosine kinases
• Several growth factors stimulate receptor

tyrosine kinases
- Insulin
- Insulin-like growth factor-1
- Fibroblast growth factor
- Epidermal growth factor
- Nerve growth factor

Table 14-3

Receptor Tyrosine Kinases Aggregate
and Undergo Autophosphorylation
• Many receptor tyrosine kinases (RTKs) trigger a
chain of events in the cell that culminate in cell
growth, proliferation, or specialization

Figure 14-16

The Structure of Receptor Tyrosine
Kinases
• Receptor tyrosine kinases often consist of a single
polypeptide chain with just one transmembrane
segment
• The extracellular part of the receptor contains the

ligand-binding domain
• On the cytosolic side is the tyrosine kinase domain

Structure of receptor tyrosine kinases
• Sometimes the receptor and tyrosine kinase are

two separate proteins
• In this case the nonreceptor tyrosine kinase binds

to the receptor and is activated in response to
ligand binding
• E.g., Src was the first nonreceptor tyrosine kinase

discovered
The Activation of Receptor Tyrosine
Kinases
• Signal transduction is initiated upon ligand binding
that causes aggregation of receptor tyrosine
kinases
• In some cases, receptors dimerize upon ligand

binding, and phosphorylate each other
• Because they phosphorylate the same type of

receptor as themselves, this is called
autophosphorylation
Disruptions of Growth Factor Signaling
Can Lead to Cancer
• Some cancers can result from the loss of
regulation of growth factor signaling
• E.g., mutations in Ras are often associated with

cancer

Diabetes
• Type I diabetes results in loss of insulin-producing

cells in the islets of Langerhans
• It can be successfully treated with insulin
• Type II diabetes appears to result from resistance

to insulin and so is not effectively treated with
insulin

Insulin
• Insulin has rapid and longer-lasting effects on a

variety of cells
• Insulin binds to receptor tyrosine kinases, which

have two  and two  subunits
• When insulin binds the receptor, the  subunits

phosphorylate insulin receptor substrate I (IRS-1)

Insulin signaling (continued)
• Phosphorylated IRS-1 stimulates two different

pathways
• IRS-1 can recruit GRB2, activating the Ras

pathway (1)
• IRS-1 can also bind

phosphatidylinositol-3-kinase (PI 3-kinase),
which converts PIP2 into PIP3 (2)
Figure 14-23

• PIP3 binds a protein called Akt (or protein

kinase B) (3)
• An enzyme that opposes P1 3-kinase is PTEN, a

phosphatase that removes a phosphate from PIP3,
preventing activation of Akt
• Activation of Akt has two important consequences

• Activation of Akt leads to movement of a glucose

transporter, GLUT4, to the plasma membrane,
allowing glucose uptake
• Also, Akt can phosphorylate glycogen synthase

kinase 3 (GSK3), reducing its activity
• This leads to an increase in the amount of the

active form of glycogen synthase, enhancing
glycogen production

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MEDICAL

© 2012 Pearson Education, Inc.

1. Human Physiology, 6th ed. Berne & Levy

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3. Some blood coagulation reactions are autocatalytic

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• Cellular adaptation occurs by any of the

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• Dysplasia is the condition characterized by

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• Answer: It is the same as anticipatory

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C. Autocrine signaling. Cells respond to signaling molecules that

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• Classification of signaling molecules

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Gap junctions Plasmodesmata

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Target cell Electrical signal Endocrine cell Blood

Paracrine signaling Synaptic signaling

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