1.

Explain the structure of the lipid bilayer of the cell membrane, it’s synthesis, and
characteristics

Structure of Plasma Membranes

The plasma membrane (also known as the cell membrane or cytoplasmic membrane) is a biological
membrane that separates the interior of a cell from its outside environment.

The primary function of the plasma membrane is to protect the cell from its surroundings. Composed
of a phospholipid bilayer with embedded proteins, the plasma membrane is selectively permeable to
ions and organic molecules and regulates the movement of substances in and out of cells. Plasma
membranes must be very flexible in order to allow certain cells, such as red blood cells and white
blood cells, to change shape as they pass through narrow capillaries.

The plasma membrane also plays a role in anchoring the cytoskeleton to provide shape to the cell,
and in attaching to the extracellular matrix and other cells to help group cells together to form tissues.
The membrane also maintains the cell potential.

In short, if the cell is represented by a castle, the plasma membrane is the wall that provides structure
for the buildings inside the wall, regulates which people leave and enter the castle, and conveys
messages to and from neighboring castles. Just as a hole in the wall can be a disaster for the castle,
a rupture in the plasma membrane causes the cell to lyse and die.

The plasma membrane

The plasma membrane is composed of phospholipids and proteins that provide a barrier

between the external environment and the cell, regulate the transportation of molecules across

the membrane, and communicate with other cells via protein receptors.

The Plasma Membrane and Cellular

Transport
The movement of a substance across the selectively permeable plasma membrane can be either
"passive"—i.e., occurring without the input of cellular energy—or "active"—i.e., its transport requires
the cell to expend energy.

The cell employs a number of transport mechanisms that involve biological membranes:

1. Passive osmosis and diffusion: transports gases (such as O2 and CO2) and other small
molecules and ions
2. Transmembrane protein channels and transporters: transports small organic molecules such
as sugars or amino acids
 3. Endocytosis: transports large molecules (or even whole cells) by engulfing them
4. Exocytosis: removes or secretes substances such as hormones or enzymes

The Plasma Membrane and Cellular Signaling

Among the most sophisticated functions of the plasma membrane is its ability to transmit signals via
complex proteins. These proteins can be receptors, which work as receivers of extracellular inputs
and as activators of intracellular processes, or markers, which allow cells to recognize each other.

Membrane receptors provide extracellular attachment sites for effectors like hormones and growth
factors, which then trigger intracellular responses. Some viruses, such as Human Immunodeficiency
Virus (HIV), can hijack these receptors to gain entry into the cells, causing infections.

Membrane markers allow cells to recognize one another, which is vital for cellular signaling processes
that influence tissue and organ formation during early development. This marking function also plays
a later role in the "self"-versus-"non-self" distinction of the immune response. Marker proteins on
human red blood cells, for example, determine blood type (A, B, AB, or O).

The fluid mosaic model describes the plasma membrane structure as a mosaic
of phospholipids, cholesterol, proteins, and carbohydrates.

The fluid mosaic model was first proposed by S.J. Singer and Garth L.

Nicolson in 1972 to explain the structure of the plasma membrane. The

model has evolved somewhat over time, but it still best accounts for the

structure and functions of the plasma membrane as we now understand

them. The fluid mosaic model describes the structure of the plasma

membrane as a mosaic of components —including phospholipids,

cholesterol, proteins, and carbohydrates—that gives the membrane a fluid

character . Plasma membranes range from 5 to 10 nm in thickness. For

comparison, human red blood cells, visible via light microscopy, are

approximately 8 µm wide, or approximately 1,000 times wider than a

plasma membrane. The proportions of proteins, lipids, and carbohydrates

in the plasma membrane vary with cell type. For example, myelin contains

18% protein and 76% lipid. The mitochondrial inner membrane contains

76% protein and 24% lipid.

The Components and functions of the Plasma Membrane

The principal components of a plasma membrane are lipids (phospholipids and cholesterol),
proteins, and carbohydrates attached to some of the lipids and some of the proteins.

The fluid mosaic model of the plasma membrane

The fluid mosaic model of the plasma membrane describes the plasma membrane as a fluid
combination of phospholipids, cholesterol, and proteins. Carbohydrates attached to lipids
(glycolipids) and to proteins (glycoproteins) extend from the outward-facing surface of the
membrane.
The main fabric of the membrane is composed of amphiphilic or dual-

loving, phospholipid molecules. The hydrophilic or water-loving areas of

these molecules are in contact with the aqueous fluid both inside and

outside the cell. Hydrophobic, or water-hating molecules, tend to be non-

polar. A phospholipid molecule consists of a three-carbon glycerol

backbone with two fatty acid molecules attached to carbons 1 and 2, and a

phosphate-containing group attached to the third carbon. This

arrangement gives the overall molecule an area described as its head (the

phosphate-containing group), which has a polar character or negative

charge, and an area called the tail (the fatty acids), which has no charge .

They interact with other non-polar molecules in chemical reactions, but

generally do not interact with polar molecules. When placed in water ,

hydrophobic molecules tend to form a ball or cluster. The hydrophilic

regions of the phospholipids tend to form hydrogen bonds with water and

other polar molecules on both the exterior and interior of the cell. Thus, the

membrane surfaces that face the interior and exterior of the cell are

hydrophilic. In contrast, the middle of the cell membrane is hydrophobic

and will not interact with water. Therefore, phospholipids form an excellent

lipid bilayer cell membrane that separates fluid within the cell from the

fluid outside of the cell.

Phospholipid aggregation

In an aqueous solution, phospholipids tend to arrange themselves with their polar heads facing
outward and their hydrophobic tails facing inward.
The structure of a phospholipid molecule

This phospholipid molecule is composed of a hydrophilic head and two hydrophobic tails. The
hydrophilic head group consists of a phosphate-containing group attached to a glycerol
molecule. The hydrophobic tails, each containing either a saturated or an unsaturated fatty
acid, are long hydrocarbon chains.

Proteins make up the second major component of plasma membranes.

Integral proteins (some specialized types are called integrins) are, as their
name suggests, integrated completely into the membrane structure, and

their hydrophobic membrane-spanning regions interact with the

hydrophobic region of the the phospholipid bilayer . Single-pass integral

membrane proteins usually have a hydrophobic transmembrane segment

that consists of 20–25 amino acids. Some span only part of the

membrane—associating with a single layer—while others stretch from one

side of the membrane to the other, and are exposed on either side. Some

complexproteins are composed of up to 12 segments of a single protein,

which are extensively folded and embedded in the membrane. This type of

protein has a hydrophilic region or regions, and one or several mildly

hydrophobic regions. This arrangement of regions of the protein tends to

orient the protein alongside the phospholipids, with the hydrophobic region

of the protein adjacent to the tails of the phospholipids and the hydrophilic

region or regions of the protein protruding from the membrane and in

contact with the cytosol or extracellular fluid.

Structure of integral membrane proteins

Integral membrane proteins may have one or more alpha-helices that span the membrane
(examples 1 and 2), or they may have beta-sheets that span the membrane (example 3).

Carbohydrates are the third major component of plasma membranes. They

are always found on the exterior surface of cells and are bound either to

proteins (forming glycoproteins) or to lipids (forming glycolipids). These

carbohydrate chains may consist of 2–60 monosaccharide units and can be

either straight or branched. Along with peripheral proteins, carbohydrates

form specialized sites on the cell surface that allow cells to recognize each

other. This recognition function is very important to cells, as it allows the

immune system to differentiate between body cells (called "self") and

foreign cells or tissues (called "non-self"). Similar types of glycoproteins

and glycolipids are found on the surfaces of viruses and may change

frequently, preventing immune cells from recognizing and attacking them.

These carbohydrates on the exterior surface of the cell—the carbohydrate

components of both glycoproteins and glycolipids—are collectively referred

to as the glycocalyx (meaning "sugar coating"). The glycocalyx is highly

hydrophilic and attracts large amounts of water to the surface of the cell.

This aids in the interaction of the cell with its watery environment and in

the cell's ability to obtain substances dissolved in the water.

Source: Boundless. “Components of Plasma Membranes.” Boundless Biology. Boundless, 08 Aug.

2016. Retrieved 22 Nov. 2016 from https://www.boundless.com/biology/textbooks/boundless-biology-
textbook/structure-and-function-of-plasma-membranes-5/components-and-structure-64/components-
of-plasma-membranes-326-11463/

Source: Boundless. “Fluid Mosaic Model.” Boundless Biology. Boundless, 26 May. 2016. Retrieved 22
Nov. 2016 from https://www.boundless.com/biology/textbooks/boundless-biology-textbook/structure-
and-function-of-plasma-membranes-5/components-and-structure-64/fluid-mosaic-model-327-11464/

2. Describe the incorporation of membrane proteins and carbohydrate layers on the lipid
bilayer structure of the cell membrane.

Different membrane proteins are associated with the membranes in different ways, as
illustrated in Figure 10-17. Many extend through the lipid bilayer, with part of their mass on
either side (examples 1, 2, and 3 in Figure 10-17). Like their lipid neighbors, these
transmembrane proteins are amphipathic, having regions that are hydrophobic and regions
that are hydrophilic. Their hydrophobic regions pass through the membrane and interact with
the hydrophobic tails of the lipid molecules in the interior of the bilayer, where they are
sequestered away from water. Their hydrophilic regions are exposed to water on either side
of the membrane. The hydrophobicity of some of these transmembrane proteins is increased
by the covalent attachment of a fatty acid chain that inserts into the cytosolic monolayer of
the lipid bilayer (example 1 in Figure 10-17).

Figure 10-17
 Various ways in which membrane proteins associate with the lipid bilayer. Most trans-
membrane proteins are thought to extend across the bilayer as (1) a single α helix, (2) as
multiple α helices, or (3) as a rolled-up β sheet (a (more...)
Other membrane proteins are located entirely in the cytosol and are associated with the
cytosolic monolayer of the lipid bilayer either by an amphipathic α helix exposed on the
surface of the protein (example 4 in Figure 10-17) or by one or more covalently attached
lipid chains, which can be fatty acid chains or prenyl groups (example 5 in Figure 10-17
and Figure 10-18). Yet other membrane proteins are entirely exposed at the external cell
surface, being attached to the lipid bilayer only by a covalent linkage (via a specific
oligosaccharide) to phosphatidylinositol in the outer lipid monolayer of the plasma
membrane (example 6 in Figure 10-17).

Figure 10-18
Membrane protein attachment by a fatty acid chain or a prenyl group. The covalent
attachment of either type of lipid can help localize a water-soluble protein to a membrane
after its synthesis in the cytosol. (A) A fatty acid chain (myristic acid) is (more...)
The lipid-linked proteins in example 5 in Figure 10-17 are made as soluble proteins in the
cytosol and are subsequently directed to the membrane by the covalent attachment of a
lipid group (see Figure 10-18). The proteins in example 6, however, are made as single-
pass transmembrane proteins in the ER. While still in the ER, the transmembrane
segment of the protein is cleaved off and a glycosylphosphatidylinositol (GPI) anchor
is added, leaving the protein bound to the noncytosolic surface of the membrane solely
by this anchor (discussed in Chapter 12). Proteins bound to the plasma membrane by a
GPI anchor can be readily distinguished by the use of an enzyme called
phosphatidylinositol-specific phospholipase C. This enzyme cuts these proteins free from
their anchors, thereby releasing them from the membrane.
Some membrane proteins do not extend into the hydrophobic interior of the lipid bilayer
at all; they are instead bound to either face of the membrane by noncovalent interactions
with other membrane proteins (examples 7 and 8 in Figure 10-17). Many of the proteins
of this type can be released from the membrane by relatively gentle extraction
 procedures, such as exposure to solutions of very high or low ionic strength or of
extreme pH, which interfere with protein-protein interactions but leave the lipid bilayer
intact; these proteins are referred to as peripheral membrane proteins. Transmembrane
proteins, many proteins held in the bilayer by lipid groups, and some proteins held on the
membrane by unusually tight binding to other proteins cannot be released in these ways.
These proteins are called integral membrane proteins.
How a membrane protein associates with the lipid bilayer reflects the function of the
protein. Only transmembrane proteins can function on both sides of the bilayer or
transport molecules across it. Cell-surface receptors are transmembrane proteins that
bind signal molecules in the extracellular space and generate different intracellular
signals on the opposite side of the plasma membrane. Proteins that function on only one
side of the lipid bilayer, by contrast, are often associated exclusively with either the lipid
monolayer or a protein domain on that side. Some of the proteins involved in intracellular
signaling, for example, are bound to the cytosolic half of the plasma membrane by one or
more covalently attached lipid groups.
4. Ion Transport Mechanism

Ion transport

The movement of ions across the cell membrane is essential for many biological processes,
such as the transfer of signals through neurones, the stimulation of skeletal muscle and the
production of healthy mucus. As with all small molecules, ions can either move across the
cell membrane down their concentration gradient (through facilitated diffusion) or against it
(through active transport). The lipid bilayer is impermeable to ions and so they must rely on
transport proteins to move them across the cell membrane. These transport proteins can be
grouped into several different types: ion channels, carrier proteins and ion pumps.

All ion transporting proteins have a membrane spanning region mostly composed of α-
helices. These are made up of amino acids with hydrophobic side chains which stick out of
the side of the helix and anchor the protein to the lipid membrane through hydrophobic
interactions. The hydrophilic peptide groups are on the inside of the protein, allowing ions to
lose their water shell when entering the protein and form electrostatic interactions with the
peptide groups
instead.
Ion channels These move ions down their concentration gradient and are the fastest type
of transport protein as they do not need to undergo a conformational change. Ion channels
can be highly selective (e.g. only transporting Na+ ions) or more general, such as allowing
through any cation. There are two main types of ion channels: gated and non-gated. Non-
gated channels, such as the K+ channels involved in maintaining resting potential in
neurones, allow ions through at all times, provided there is a concentration gradient for them
to move down. Gated channels will only ‘open’ under the correct circumstances, such as a
certain membrane potential (voltage gated channels) or when an activating ligand binds to
the channel (ligand gated channels).

How can ion channels be so specific? Ion channels rely partly on the size of ions
(ionic radius) to determine which ion can pass through them- e.g. Na+ ions are smaller than
K+ ions and the Na+ ion channel pore is too small for K+ ions to pass through easily.
However, this is little use for distinguishing between ions of a similar radius such as Na+ and
Ca2+ or for K+ channels, as the smaller Na+ ions could easily fit through the pore in a K+
channel. Instead, channels use a selectivity filter to determine which ion can pass through
the pore. This is a series of a few, highly conserved, amino acids at the entrance to the pore,
one on each subunit (e.g. in K+ channels the selectivity filter is the series Thr-Val-Gly-Tyr-
Gly).
 When ions enter a channel pore they must first lose their shell of water molecules and form
new electrostatic interactions with the oxygen atoms of the carbonyl groups in the selectivity
filter. It requires energy for an ion to lose its water shell so this will only happen if the new
interactions it forms are more energetically favourable. In the case of the K+ channel, the
oxygen atoms of the selectivity filter are ideally positioned to form interactions with K+ ions
but not with Na+ ions as they are too small. This makes it energetically unfavourable for Na+
ions to
enter a K+
channel
and so it
is very
unlikely to
occur.

6. Describe the mechanism of function and control of Calcium, Chloride and Sodium ion
channels.
· Voltage-gated Calcium channel
Voltage-gated calcium channels are the primary mediators of depolarization-
induced calcium entry into neurons. There is great diversity of calcium channel
subtypes due to multiple genes that encode calcium channel α1 subunits, co-
assembly with a variety of ancillary calcium channel subunits, and alternative
splicing.
They are activated (opened) at depolarized membrane potentials and this is the
source of the "voltage-dependent" epithet. The concentration of calcium (Ca2+
ions) is normally several thousand times higher outside of the cell than inside.
Activation of particular VDCCs allows Ca2+ to rush into the cell, which, depending
on the cell type, results in activation of calcium-sensitive potassium channels,
muscular contraction, excitation of neurons, up-regulation of gene expression, or
release of hormones or neurotransmitters.
Voltage-dependent calcium channels are formed as a complex of several different
subunits: α1, α2δ, β1-4, and γ.
 · Voltage-gated Chloride channels channel
Voltage-gated chloride channels display a variety of important physiological and
cellular roles that include regulation of pH, volume homeostasis, organic solute
transport, cell migration, cell proliferation and differentiation. Based on sequence
homology the chloride channels can be subdivided into a number of groups.
Voltage-gated chloride channels are important for setting cell resting membrane
potential and maintaining proper cell volume. These channels conduct Cl− as well
as other anions such as HCO−3, I−, SCN−, and NO−3. The structure of these
channels are not like other known channels. The chloride channel subunits
contain between 1 and 12 transmembrane segments. Some chloride channels are
activated only by voltage (voltage-gated), while others are activated by Ca2+, other
extracellular ligands, or pH.
· Voltage-gated Sodium channel
Voltage-gated sodium channels play an important role in action potentials. If
enough channels open when there is a change in the cell's membrane potential,
a small but significant number of Na+ ions will move into the cell down their
electrochemical gradient, further depolarizing the cell.
Voltage-gated Na+ channels have three main conformational states: closed, open
and inactivated. Forward/back transitions between these states are
correspondingly referred to as activation/deactivation (between closed and open),
inactivation/reactivation (between open and inactivated), and recovery from
inactivation/closed-state inactivation (between inactivated and closed). Closed and
inactivated states are ion impermeable.

7. Heritable diseases associated with ion channel mutations

The following table lists some well-defined disorders associated with defects in ion channels.

Ion channel diseases

Syndrome Inheritance
R=recessive
D=dominant
XL = X-linked
A=autosomal
Myotonia congenita (Thomsen's disease) AD
Periodic paralyses (hyper- & hypokalaemic) AD
Malignant hyperthermia AD
Long QT syndrome AD / AR
Cystic fibrosis AR
Heritable hypertension (Liddle's syndrome) AR
Familial persistent hyperinsulinaemic hypoglycaemia of infancy AR
Generalised myotonia (Becker's disease) AR
Hereditary nephrolithiasis (Dent's disease) XL
Masseter muscle rigidity ?
Central core disease ?
Cystic fibrosis (CF)
Manifestations of CF stem from a defect in the chloride-channel protein (CFTR) that
prevents chloride crossing the cell membrane. Chloride channels situated at the apex of
epithelial cells hinder the egress of chloride ions into the lumen. Control of sodium channels
is also lost, increasing the reabsorption of sodium from the lumen. The result is thick,
desiccated mucus - a primary clinical characteristic of the disease.

1 in 2500 – 3000 white persons is born with CF, and more than 450 mutations have been
identified in CFTR. A deletion of phenylalanine at position 508 (DeltaF508) accounts for
more than 70% of cases and is associated with severe pancreatic insufficiency and
pulmonary disease. DF508 CFTR channel conducts chloride well once it is incorporated into
a cell membrane. However, the mutant protein becomes stuck in intracellular organelles due
to improper folding and is not inserted into the cell membrane.

Potential molecular strategies to treat CF include replacing the mutant chloride channel by
gene therapy or protein delivery; improving secretion from the mutant CFTR protein with
CFTR-channel openers; "chaperonins" which allow for proper incorporation of CFTR into the
cell membrane; bypassing CFTR defect by activating other chloride channels; and blocking
increased sodium reabsorption through sodium channels using aerosolised amiloride. Only
the last therapy is currently in common clinical use.

Long QT syndrome
Disorder of cardiac repolarisation characterised by QT interval prolongation & T wave
abnormalities that results in ventricular arrhythmias with syncope and sudden death in
children and young adults. The exact aetiology of the disease was unclear for a long time but
in the early 1990's researchers demonstrated convincingly that the disease is inherited. It
was subsequently determined to be genetically heterogeneous, with six different genes
being implicated. Further work elucidated the responsible mutations and showed that defects
in particular ion channels lead to the long QT syndrome.

LQTS1 is linked to chromosome 11. Chromosomes 7 and 3 are implicated in LQTS2 and
LQTS3 respectively. LQTS1 and LQTS2 are due to a defect in the cardiac potassium
channel gene whereas a defective sodium channel gene causes LQTS3.

The gene linked to chromosome 7 has been labelled as the human ether-a-go-go-related
gene (HERG). This is a potassium channel gene related to the drosophila ether-a-go-go
(eag) gene, from which it was cloned. The eag locus is involved in the control of potassium
currents in the membranes of drosophila nerve & muscle. Mutants in this locus display ether-
induced leg shaking, hence the name “ether-a-go-go”. Mutations in HERG are responsible
for LQTS2. In normal cardiac physiology HERG suppresses depolarisations that lead to
premature firing. Subjects with LQTS2 lack protection from arrhythmogenic afterbeats and
may be prone to sudden cardiac death.

Drugs which cause LQTS do so by blocking the potassium channels that are involved in
LQTS1 and LQTS2. Examples of these drugs are:

Quinidine, Sotalol, Erythromycin, Trimethoprim & sulfamethoxazole

Cardiac repolarisation (T wave) occurs as a result of ion currents controlled by potassium

channels. In LQTS there is a delay in the opening of channels, which prolongs the action
potential, causing a prolonged QT interval. These patients have a propensity to torsade de
pointes and ventricular tachycardia.

The inherited LQTS presents in one of 2 forms:

Jervell, Lange-Nielsen variant (rare) associated with congenital deafness.

Romano-Ward variant (more common; AR) with normal hearing.
Myotonic diseases
These are a group of clinically similar diseases that share the feature of myotonia: delayed
muscle relaxation after voluntary contraction or mechanical stimulation. e.g. hyperkalaemic
periodic paralysis (HKPP), paramyotonia congenita, myotonia congenita and myotonic
dystrophy.

HKPP
Transient episodes of paralysis; AD; attacks of paralysis are frequent, brief and precipitated
by rest after exercise, stress and ingestion of certain foods and potassium. Due to defective
sodium channels.

Paramyotonia congenita
Cold-induced, there is prolonged, localised myotonia and weakness. Muscle activity
aggravates the myotonia associated with paramyotonia congenita (paradoxical myotonia), in
contrast to the improvement of symptoms seen with exercise in most patients with myotonic
disorders (classic myotonia). Due to defective sodium channels.

Myotonia congenita
In this disorder muscle stiffness resolves with exercise. The autosomal dominant variant is
"Thomsen's disease". The continual 'isometric exercise' that these individuals undergo gives
them the habitus of a 'circus strongman', at least in their earlier years. The defect is in a
chloride channel, as is the case with the autosomal recessive form, termed Becker's
disease.

Malignant hypermetabolic syndrome ('Malignant hyperthermia', MH)

This is not a disease in the strict sense of the word, but a genetic predisposition of clinically
inconspicuous individuals to respond abnormally when exposed to volatile anaesthetics or
depolarizing muscle relaxants. It is a drug-induced, potentially lethal event in carriers of
calcium channel mutations. A pathologically large increase in myoplasmic Ca++
concentration following exposure to triggering agents is seen in these patients. This causes
an increase muscle metabolism and heat production resulting in symptoms of muscle
rigidity, hyperthermia, metabolic acidosis, hyperkalaemia & hypoxia. Dantrolene, an inhibitor
of calcium release from the SR is used to abort the crisis.

MH susceptibility in humans is genetically heterogeneous. The gene encoding the skeletal

muscle ryanodine receptor (a calcium channel) is the villain in some families. To date, more
than 20 disease-causing point mutations have been identified in humans. 2 mutations in the
dihydropyridine receptor have also been described.

The malignant hypermetabolic syndrome is discussed in detail elsewhere on this website .

Central core disease (CCD)
This is allelic to MH. It is a congenital AD proximal myopathy with structural alterations of
certain muscle fibre types. These patients are hypotonic at birth but muscle strength usually
improves later in life. In spite of the fact that events similar to MH may occur in numerous
muscle disorders during general anaesthesia, a genetic relation exists with certainty only in
CCD and possibly in King-Denborough syndrome.

8. Cell membrane abnormalities that occur in cystic fibrosis

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

CFTR is an integral membrane protein that functions as an epithelial anion channel. The ~1480-
amino-acid molecule encodes a passive conduit for chloride and bicarbonate transport across
plasma membranes of epithelial tissues, with direction of ion flow dependent on the
electrochemical driving force. Gating of CFTR involves conformational cycling between an open
and closed configuration and is augmented by hydrolysis of adenosine triphosphate (ATP). Anion
flux mediated by CFTR does not involve active transport against a concentration gradient but
utilizes the energy provided from ATP hydrolysis as a central feature of ion channel
mechanochemistry and gating.

CFTR is situated in the apical plasma membranes of acinar and other epithelial cells where it
regulates the amount and composition of secretion by exocrine glands. In numerous epithelia,
chloride and bicarbonate release is followed passively by the flow of water, allowing for
mobilization and clearance of exocrine products. Along respiratory mucosa, CFTR is necessary
to provide sufficient depth of the periciliary fluid layer (PCL), allowing normal ciliary extension and
mucociliary transport. CFTR-deficient airway cells exhibit depleted PCL, causing ciliary collapse
and failure to clear overlying mucus. In airway submucosal glands, CFTR is highly expressed in
acini and may participate both in the formation of mucus and extrusion of glandular secretion
onto the airway surface. In other exocrine glands characterized by abrogated mucus transport
(e.g., pancreatic acini and ducts, bile canaliculi, intestinal lumen), similar pathogenic mechanisms
have been implicated. In these tissues, a driving force for apical chloride and/or bicarbonate
secretion is believed to promote CFTR-mediated fluid and electrolyte release into the lumen,
which confers proper rheology of mucins and other exocrine products. Failure of this mechanism
disrupts normal hydration and transport of glandular secretion and is widely viewed as a
proximate cause of ductular obstruction, with concomitant tissue injury.

CFTR defects known to elicit disease are often categorized based on molecular mechanism. For
example, the common F508del mutation (nomenclature denotes omission of a single
phenylalanine residue [F] at CFTR position 508) leads to a folding abnormality recognized by
 cellular quality control pathways. CFTR encoding F508del retains partial ion channel function, but
protein maturation is arrested in the endoplasmic reticulum, and CFTR fails to arrive at the
plasma membrane. Instead, F508del CFTR is misrouted and undergoes endoplasmic reticulum–
associated degradation via the proteasome. CFTR mutations that disrupt protein maturation are
termed class II defects and are by far the most common genetic abnormalities. F508del alone
accounts for ~70% of defective CFTRalleles in the United States, where approximately 90% of
individuals with CF carry at least one F508del mutation.

9. Correlate the clinical symptoms of CF with the abnormalities of the cell membrane
· The most common symptoms of cystic fibrosis are coughing and chronic breathing

difficulties caused by the build-up of sticky mucus in the lungs and respiratory tubes.

· Recurring lung infections are very common and in the long term this can result in lung

scarring, called fibrosis.

· The damage caused by this fibrosis and thick mucus damages the airways of the lungs. In

turn, this leads to a tendency toward more infections and decreased lung function.

· In 85 per cent of cystic fibrosis cases, sufferers also have a deficiency in their pancreas

caused by thick mucus blocking the pancreatic ducts. This prevents the pancreas from

delivering enzymes needed for digestion, and from producing insulin?, which can lead to

diabetes?. Children with this aspect of the disease suffer from malnutrition? and struggle to

put on weight.

· Almost all males with cystic fibrosis are infertile because the tubes that transport sperm (vasa

deferentia) are usually missing.

10. Role of ion channel in cell signalling in nerve cells.

Action Potential

As long as the stimuli does not cause the membrane potential to reach -50 mV, only a passive

current that diminishes with time and distance is generated through the neuron. However, if

the stimuli is enlarged or additional stimuli is provided to the cell, a depolarization of more

than 15 to 20 mV may occur (this is possible because the current is proportional to the size of

the simuli).
A. Depolarization

If a passive potential depolarizes the membrane to about -50 mV, all Na+ voltage-gated

channels are opened:

A combination of diffusion and electrostatic pressure causes a sudden rushing in, or influx, of

Na+ ions into the neuron's intracellular fluid

This causes a further depolarization of the membrane, and more Na+ voltage-gated channels

are opened

This is a rapid self-reinforcing cycle (which lasts about 25ms) that continues until all Na+

voltage-gated channels are opened. It is known as the Hodgkin-Huxley Cycle

Because the membrane has suddenly become 100% permeable, its membrane potential

becomes very positive inside the neuron, about +50 mV.

This massive depolarization is digital, i.e. all or none, and is independent of the stimulation

intensity

B. Absolute Refractory Period

The moment the membrane potential hits +50 mV, all the Na+ voltage-gated channels are

closed and the K+ voltage-gated channels are opened:

This causes K+ ions to flow out, or efflux, of the neuron, thereby causing a repolarization of

the membrane. This period from the time the Na+ voltage-gated channels are closed and the

K+ voltage-gated channels are opened to the time when the K+ voltage-gated channels are

closed again, is called the absolute refractory period

During the absolute refractory period no further action potential can occur:

The Na+ voltage-gated channels are completely closed

Hence the membrane cannot be depolarizated with an influx of Na+ ions

 C. Relative Refractory Period

After the absolute refractory period, there is a period when both Na+ and K+ voltage-gated

channels remain closed:

This causes the membrane potential to be even more negative than at rest

The membrane potential is now hyperpolarized ("hyper" means extra, super)

It would take more stimuli to bring the potential to threshold in order to create another action

potential

This period is called the relative refractory period

Sections A, B, and C above are depicted graphically in the diagram below:

Glucosa regulator

Insulin and glucagon are potent regulators of glucose metabolism. For decades, we have viewed

diabetes from a bi-hormonal perspective of glucose regulation. This perspective is incomplete

and inadequate in explaining some of the difficulties that patients and practitioners face when

attempting to tightly control blood glucose concentrations. Intensively managing diabetes

with insulin is fraught with frustration and risk. Despite our best efforts, glucose fluctuations

are unpredictable, and hypoglycemia and weight gain are common. These challenges may be

a result of deficiencies or abnormalities in other glucoregulatory hormones. New

understanding of the roles of other pancreatic and incretin hormones has led to a multi-

hormonal view of glucose homeostasis.

HISTORICAL PERSPECTIVE

Our understanding of diabetes as a metabolic disease has evolved significantly since the

discovery of insulin in the 1920s. Insulin was identified as a potent hormonal regulator of

both glucose appearance and disappearance in the circulation. Subsequently, diabetes was

viewed as a mono-hormonal disorder characterized by absolute or relative insulin deficiency.

Since its discovery, insulin has been the only available pharmacological treatment for patients
with type 1 diabetes and a mainstay of therapy for patients with insulin-deficient type 2

diabetes.1–7

The recent discovery of additional hormones with glucoregulatory actions has expanded our

understanding of how a variety of different hormones contribute to glucose homeostasis. In

the 1950s, glucagon was characterized as a major stimulus of hepatic glucose production.

This discovery led to a better understanding of the interplay between insulin and glucagon,

thus leading to a bi-hormonal definition of diabetes. Subsequently, the discovery of a second

β-cell hormone, amylin, was first reported in 1987. Amylin was determined to have a role

that complemented that of insulin, and, like insulin, was found to be deficient in people with

diabetes. This more recent development led to a view of glucose homeostasis involving
multiple pancreatic hormones.8

In the mid 1970s, several gut hormones were identified. One of these, an incretin hormone,

glucagon-like peptide-1 (GLP-1), was recognized as another important contributor to the

maintenance of glucose homeostasis.9,10 Based on current understanding, glucose

homeostasis is governed by the interplay of insulin, glucagon, amylin, and incretin hormones.

This enhanced understanding of glucose homeostasis will be central to the design of new

pharmacological agents to promote better clinical outcomes and quality of life for people

with diabetes. This review will focus on the more recently discovered hormones involved in

glucose homeostasis and is not intended to be a comprehensive review of diabetes therapies.

NORMAL PHYSIOLOGY

Plasma glucose concentration is a function of the rate of glucose entering the circulation

(glucose appearance) balanced by the rate of glucose removal from the circulation (glucose

disappearance). Circulating glucose is derived from three sources: intestinal absorption

during the fed state, glycogenolysis, and gluconeogenesis. The major determinant of how
quickly glucose appears in the circulation during the fed state is the rate of gastric emptying.

Other sources of circulating glucose are derived chiefly from hepatic processes:

glycogenolysis, the breakdown of glycogen, the polymerized storage form of glucose; and

gluconeogenesis, the formation of glucose primarily from lactate and amino acids during the

fasting state.

Glycogenolysis and gluconeogenesis are partly under the control of glucagon, a hormone

produced in the α-cells of the pancreas. During the first 8–12 hours of fasting, glycogenolysis

is the primary mechanism by which glucose is made available (Figure 1A). Glucagon

facilitates this process and thus promotes glucose appearance in the circulation. Over longer

periods of fasting, glucose, produced by gluconeogenesis, is released from the liver.