Unit 1 – Introduction and Review

1. physiology, homeostasis

2. cell-cell communication revisited

3. G-protein signaling and cholera

4. Cannon’s Postulates and homeostatic reflex pathways

 What is Physiology?

long answer:
“the science of the mechanical, physical, bioelectrical,
and biochemical functions of < organism of interest > in
good health, their organs, and the cells of which they
are composed”

shorter answer:
“the science of the function of living systems”
 Function versus Process

• Function → “why”
– Why does the system exist?
– Why does the event occur?

• Process → “how”
– How does a system work?
• physiological mechanisms
 Function and Process
HOW do we break down nutrients and deliver them to tissues/cells?

WHY do we need to eat?

HOW do RBCs transport oxygen?

WHY do cells and tissues use oxygen?

HOW do we breathe?

WHY do we need to breathe?

 Homeostasis
• maintenance of a relatively stable internal environment
(especially extracellular fluid)
– oscillation around a set point

external extracellular intracellular

environment fluid (ECF) fluid

12 L interstitial 25 L in cells
+ 3 L plasma

40 L total fluid
Fig. 1.5
 Historical Interlude
1854, Claude Bernard “la fixité du milieu intérieur”

1929, Walter Cannon “homeostasis”

‘homeo’ rather than homo → similar, though not the same

Walter Cannon 1871-1945

- “flight or fight response”

- expanded on Bernard’s
concept of homeostasis

published in 1932,
$32 on amazon.ca
 Organism in
homeostasis

External Internal
change change

study of homeostatic mechanisms

Internal change = physiology
results in loss
of homeostasis
failure to compensate for change
= disease
Organism attempts
to compensate study of failure to compensate
= pathophysiology

Compensation fails Compensation succeeds

Illness or disease Wellness

Fig. 1.4
 Local versus Reflex Control
Brain evaluates
change and initiates
response.

Systemic
change in blood
pressure sensed
here.
LOCAL cells at a distant
CHANGE site control
cells near site response.
of change Blood vessels
initiate response
LOCAL REFLEX
RESPONSE RESPONSE
initiated by cells
at a distant site. KEY
Stimulus
Integrating center
Response
Fig. 1.9
 Control Systems and Homeostasis
response loop:
• stimulus, sensor, input signal, integrating centre, output
signal, target, response

feedback mechanisms:
• negative feedback stabilizes variable
• feedforward control anticipates change
• positive feedback reinforces stimulus – not homeostatic
 Unit 1 – Introduction and Review
1. physiology, homeostasis

2. cell-cell communication revisited

3. G-protein signaling and cholera

4. Cannon’s Postulates and homeostatic reflex pathways

 Cell-Cell Communication - Overview
• 75 trillion cells in the human body

• homeostasis achieved by nervous and endocrine

systems with their combination of electrical and
chemical signals

– electrical signals – changes in membrane potential

• restricted to nerve and muscle cells

– chemical signals are secreted into extracellular fluid

by all cells
• responsible for most communication

• cells that respond to signals are ‘target cells’

 Cell-Cell Communication: long range

endocrine: chemical (‘hormone’) released into

bloodstream and distributed throughout body

13

Fig. 6.1
 Cell-Cell Communication: long range
neural: electrical signal travels down neuron; reaches end and
is translated to chemical signal (neurotransmitter) which
transmits information to next cell

neuro endocrine: electrical signal travels down neuron;

reaches end and is secreted into blood

14

Fig. 6.1
 What defines a ‘target’ cell?
How can sending a signal throughout the entire body affect
only certain cells?

→ Only cells that have receptors for that signal will respond to it.
→signal molecule that binds to a particular receptor is its
ligand

→ Receptors are proteins that

→project to outside of the membrane, or
→are within the cell, in the cytoplasm

→ Chemical properties of signal molecules (ligands) determine

what type of receptor they will interact with.

water soluble = hydrophilic = lipophobic → surface receptor

water insoluble = hydrophobic = lipophilic → intracellular receptor
 Location of Receptors
Receptor in cytosol
Receptor
in nucleus

Lipophilic signal
molecules

Lipophobic signal Slower responses

molecules related to changes
in gene activity

Lipophobic signal molecule Ligand-receptor complex

Extracellular
fluid

Receptor

16
Rapid cellular
Fig. 6.3a, b
Intracellular fluid
responses
 Types of Membrane Receptors
Channel Integrin

Cell
membrane

Anchor
protein
Enzyme G protein

Cytoskeleton
Ion Enzyme-coupled G protein-coupled Integrin
channel receptor receptor (GPCR) receptor

17

Fig. 6.3c
 Signal Transduction
signal
molecule Extracellular
fluid
binds to

membrane receptor
initiates

signal transduction
by proteins ion
channel
amplifier enzymes
alter
second messenger
molecules
Intracellular
protein kinases Ca2+ fluid

phosphorylated activated Ca2+-

proteins binding proteins

response 18

Fig. 6.5b
 Modulation of Signal Pathways
• one ligand may have several different types of receptors
– explains how same signal can have different effects in
different cell types

• receptors exhibit saturation, specificity, competition for their

ligands (and molecules similar to their ligands)
– e.g. relative affinities of adrenergic receptors for epinephrine
versus norepinephrine
– e.g. agonists and antagonists competing with endogenous
ligands

• cells can change their response to signals by changing receptor

number or sensitivity
– increase → ↑ gene expression (up-regulation)
– decrease → internalize surface receptors (down-regulation)
– change receptor sensitivity → e.g. phosphorylation
19
Adrenergic Receptors on Vascular Smooth Muscle

20
More than one receptor for a particular ligand
ligand = epinephrine (fight or flight response)

-Receptor response 2-Receptor response

-Receptor 2-Receptor
Intestinal Skeletal muscle
blood vessel blood vessel

Epinephrine + -Receptor Epinephrine + 2-Receptor

Vessel constricts
Vessel dilates
21

Fig. 6.14
 Agonists and Antagonists
structurally similar molecules compete for receptor binding sites

response no response

= natural (‘native’) ligand

= similar molecule that activates receptor
AGONIST; ANALOGUE; MIMIC
= molecule that is similar enough to native ligand to bind
to receptor, but not activate it
ANTAGONIST; BLOCKER 22

similar to Fig. 6.13

 Unit 1 – Introduction and Review
1. physiology, homeostasis

2. cell-cell communication revisited

3. G-protein signaling and cholera

4. Cannon’s Postulates and homeostatic reflex

pathways
Many Diseases and Drugs Disrupt Signal Pathways

24

Table 6.1
 Cholera
• intestinal infection, Vibrio cholerae
– contaminated food (developed countries)
– contaminated water (developing countries)

• need to ingest ~100 million bacteria

– lower doses can cause infection in …
• people with reduced gastric acidity
• young children
• immune suppressed individuals

• 100,000-130,000 deaths per year

• a few bacteria survive acidity of stomach → reach small

intestine → attach to and invade intestinal epithelial cells
→ produce toxin
25
Activation of a G-Protein Coupled Receptor (GPCR)

source: Alberts, et al. (free online)

Molecular Biology of the Cell, 4th edition
Figs 15-26, 15-28
Gα-subunit turns itself off by hydrolyzing GTP.

source: Alberts, et al. (free online)

Molecular Biology of the Cell, 4th edition
Fig 15-29
 How long does a G-protein signal last?
• as long as the  and  subunits are free …
– which is as long as the Gα-subunit is bound to GTP
– normally it hydrolyzes GTP → GDP within a few seconds
and re-associates with βγ-subunits

There are serious consequences of disruptions in Gα

activation or inactivation.
Effect of Cholera Toxin on Inactivation of Gα Subunit

source: Lodish, et al. (free online)

Molecular Cell Biology, 4th edition
Fig 20-17
 Unit 1 – Introduction and Review
1. physiology, homeostasis

2. cell-cell communication revisited

3. G-protein signaling and cholera

4. Cannon’s Postulates and homeostatic reflex pathways

 Cannon’s Postulates
• the nervous system has a role in maintaining ‘fitness’ of the internal
environment
– coordinates responses that regulate blood volume, blood pressure,
osmolarity, body temp, …

• some systems are under tonic control

• some systems are under antagonistic control

• one chemical signal can have different effects in different tissues

 ‘Tonic’ Control

Tonic control regulates physiological parameters in an up-down fashion.

Electrical
signals
from Time
neuron
Change in signal rate

Increased signal rate Decreased signal rate

Time Time

33
Fig. 6.15a
 Antagonistic Control
Antagonistic neurons control heart rate:
some speed it up, while others slow it down.

Parasympathetic Sympathetic
neuron neuron

Stimulation by sympathetic nerves increases heart rate. Stimulation by parasympathetic nerves decreases heart rate.

Heart beats Heart beats

34
Fig. 6.15b
 Steps of a Reflex Pathway
STIMULUS sensors / detectors / receptors:
• specialized cell types in strategic locations
SENSOR
(often in extracellular fluid)
or
RECEPTOR
examples of signals monitored:
• chemicals - glucose, CO2, O2, Na+, Ca2+
AFFERENT

Response loop
Feedback loop

PATHWAY • hormones – via specific receptors

• osmolarity – cells that respond to swelling,
shrinking
INTEGRATING
CENTER
• blood volume/pressure – cells that respond
to stretch

EFFERENT integrating centres:

PATHWAY • organ or gland
• brain (often brain is cc’d but is not
TARGET OR
EFFECTOR
necessary for homeostatic response)

efferent output:
RESPONSE
• can be to particular cell type within an organ
or multiple organ systems 35
similar to Fig. 6.16
 Multiple Meanings of ‘Receptor’

Fig. 6.17
 Simple Simple Neural Complex Neuro-
Endocrine Reflex Reflex endocrine Reflex

Internal Internal Internal

or external or external or external
change change change

Receptor Receptor

Input signal: Input signal:

sensory neuron sensory neuron

Endocrine Nervous Nervous

system sensor- system system
integrating integrating integrating
center center center

Efferent
Output signal: Efferent neuron or
hormone neuron neurohormone

Target Target Endocrine

integrating
center
Response Response

Output signal
# 2: hormone

Target

Response
Fig. 6.18
 Neural Versus Endocrine Control

Table 6.2