Chapter I: General

Physiology

By: Dr. Abdulrahman Aqra MD MSc

Introduction:
Imagine a unicellular organism, which lives in this atmosphere. To survive, it
has to take nutrients and oxygen from the surrounding external environment
to produce the needed for its surviving energy, and then it will get rid of
waste products and carbon dioxide directly into the same external
environment.
But a multicellular organisms like us the humans contain trillions of cells,
most of which are embedded inside the organism, which makes the direct
contact with the external environment an impossible task.
So our cells exchange substances ( taking O2 and nutrients and getting rid of
CO2 and waste products) with the fluid surrounding them inside the
organism , the extracellular fluid .So the extracellular fluid actually form an
external ( to the cells ) environment , but in the same time it is found in the
interior of the body , so we call it ( internal environment). The term was
created for the first time by the great French physiologist Claud Bernard.
Please dont be confused , it is quite easy : The extracellular fluid , which is
( external to cells) form an external environment , through which the cells
exchange substances , but as far as it is inside the body we call it ( internal
environment) .
Now: Cells are in continuous contact with the extracellular fluid (the internal
environment), and such exchange to proceed normally it requires a balance
in the internal environment.
For example : Water to move in and out of cells, it does that by the (osmosis)
, Osmosis actually aims to keep a concentration balance on both sides of the
cell membrane , without such balance there would be no balance in the

whole internal environment , and so the necessary for life biochemical

processes would never proceed.
Lets see what may happen if the concentration of solutes increases above
normal in the extracellular fluid. This would causes movement of the
intracellular fluid to the extracellular and the cells will shrink. On the other
hand: If the concentration of solutes decrease in the extracellular fluid, this
will cause the movement of fluid from the extracellular fluid inside the cells,
and this will cause swelling and rupture of the cells, so the maintaining a
stable concentration of solutes in the extracellular fluid (the internal
environment) is an essential condition for surviving of cells and organism as
a whole.
Diffusion of O2 inside the cells and diffusion of CO2 outside the cells follow
the same principle. The same is true for maintaining a stable pH,
temperature, pressure..etc.
But as we know the internal balance always changes. For example: After
meal the glucose concentration increases, this will cause the pancreas to
release more Insulin to decrease the glucose concentration down to its set
point, and thus maintain a balanced glucose concentration. On the other
hand, during starvation the glucose level decreases and this will cause the
pancreas to release a hormone, called glucagon, which will increase the
glucose level in the blood up to its set point.
Such changing of glucose concentration is dynamic, and the coping of
organism with such change until re-balancing the concentration is dynamic
(going on) too. This leads us to the definition of homeostasis.

Definition of Homeostasis:
Homeostasis means: The property of human organism to maintain a dynamic
balance for its internal environment. It is derived from the Ancient Greek
language (Homoios - means: similar, and -stasis - means: standing still).
More simply it means (keeping the same). The term was created for the first
time by the Canadian physiologist Canon.

Any imbalance in the internal environment causes given mechanisms to

function in order to retain the balance, if the organism failed to achieve that,
disease will be developed and death may occur.
The eleven systems in our organism work none stop to maintain the dynamic
balance of our internal environment , as some systems control and regulate
that , so we call them regulatory systems.
The two main regulatory systems in our organism are the nervous and
endocrine system. Regulation occurs through feedback mechanism that we
will discuss shortly.
More real examples that you sense:
1- When you feel hot in a hot summer day, your organism does its best to
maintain a thermal balance by excreting more water in form of sweat and
insensible diffused water through the skin to reduce temperature, this will
decrease the body water and then stimulates the thirsty center in your brain
to make you drink more water.
2- In a cold day of winter you start to shiver , because the body temperature
decrease , and this will stimulate the thermostat in your brain which will
order your muscle to contract and produce energy to warm you up
( remember : about 80% of the muscle work serves for heating , while only
20% serves for physical work ) .
3- Pregnant ladies sometimes have a tendency to eat chalk because calcium
level decreases in their blood.
4- When you study intensively during the exam session , you feel tired and
hungry , this occurs because your brain have worked intensively and
consumed much glucose , then the glucose has decreased in your blood , so
when you take a chocolate bar you feel better , because your organism
maintained the normal level of glucose.

How homeostasis is achieved:

Homeostasis is achieved by the following steps:

A change occurs

Specific different centers detect the change, interpret, and process it

A signal to an effector is sent

The effector form a response that return thing to the set point.

All of the above mentioned steps occur through one of two feedback
mechanisms:
1- Positive feedback mechanism (more rare): This means: When a change
occurs, the organism increases the change (in other words: The organism
respond in a way that enhances the change) until forming a given response
or action.
Examples:
a- In child birth the uterine contracts, this will stimulate the hypothalamus
(part of the brain) to produce a hormone, which is called (Oxytocine),
oxytocine from its side will increase the power of uterine contraction, when
the uterine contraction is increased more, this will cause increase the
secretion of more and more oxytocine , and so on till the birth of the baby.
(Here, you may consider returning to situation before pregnancy as a set
point).
Note: Prior to child birth, the oxytocine receptors get increased in number in
the uterus.
b- After injury, the injured tissue release chemicals that activate blood
platelets, the activated platelets then release chemicals that activate more
and more platelets. The process will continue until forming a blood clot that
causes stopping of bleeding. (Stopping bleeding is returning to the set point).
2- Negative feedback mechanism (more common) : This means , when a
change occurs , the organism respond in a way that reduce the effect of
change ( reversing it and bring the organism back to normal state ) .
Examples:
a- When blood glucose increases, the pancreas releases more insulin that will
decrease blood glucose
b- When blood glucose decreases, the pancreas releases more Glucagon to
increase blood glucose.

c- When the red blood cells count decreases, the bone marrow produces
more blood cells.
d- When the potassium level increases, the adrenal cortex releases more
aldosterone which causes excretion of potassium by the kidney, decreasing
its level down to normal.
e. When the calcium level decreases, the parathyroid glands release
parathyroid hormone to increase the plasma calcium level.
f- When CO2 level increases, the respiratory center in the brain increases
frequency and depth of respiration to exhale more CO2 outside the organism
to decrease CO2 level to its set point.
g. When the blood pressure decreases, the RAAS is activated to reabsorb
more sodium and water and thus increases the blood pressure.
h. When the blood pressure decreases, the atria release atrial natriuretic
peptide, which dilates blood vessels and excretes more sodium through
urine, and thus decreases blood pressure.
i. When blood acidity increases, the buffer systems work collectively to
decrease it.
Hundreds of similar actions happen every minutes of our life, and we will
mention a lot of them during our course of Human Medical Physiology
The following image describes the negative feedback mechanism more
simply:

Note: Feed-forward mechanism is a rare mechanism that occurs when the

body anticipates (predicts) change. To clarify that imagine that the organism
expect a change and prepare itself to cope with that change. In other words:
It is not important. Don`t study it.
The systems of our organisms contribute to homeostasis each by its own, for
example: Respiratory system supplies the organism by O2, which is
necessary for burning nutrients (provided by digestive system) to produce
energy. Cardiovascular system distributes both nutrients and O2. The renal
system eliminates waste products. The integumentary system maintains
thermal and fluid-electrolytes homeostasis .During this course we will discuss
the contribution of each system in homeostasis.

Cellular level of organization

Human Physiology could be studied at many levels, including the cellular

level.
Cell is the basic structural and functional unit of the human organism which
belongs to the eukaryotic cells. Human body is composed of 100 trillions of
cells that have common universal characteristics such as:

Similar morphology (All are surrounded by cell membrane, as most of

them contain nucleus and organelles).

Cell division (with some exceptions)

Ability to synthesize protein

Ability to produce energy.

On the other hand cells differ from each others by specific characteristic due
to different functional role they play. For example:

Nerve cells have long axons to be able to transmit signals,

Glandular cells synthesize more protein

Erythrocytes have biconcave disk shape to increase the surface area

for O2 absorption.

Human cells are generally composed of:

1- The cytoplasm (a fluid medium, which contains the cellular organelles and
cytoskeleton -a supporting matrix of the cell -)
2- The nucleus (which contains the genetic material)
3- The cell membrane, which encloses the cell)
Cell is influenced by changes in its surrounding environment and reacts with
these changes to survive. So t is partially separated from its surrounding
environment by a semi-permeable plasma membrane, which enables the cell
to exchange substances with that environment and allows it to react with
and affect and be affected as well by its surrounding environment aiming to
achieve a state of dynamic balance in the internal environment of the
organism as a whole.
Cell membrane does the job by using a system of receptors, channels,
markers, and carriers that are distributed through its structure.
Keeping in mind that life is a (watery) process, so it needs boundaries to
separate two important compartments: intra- and extracellular fluids without
impairing the wise and needed communication between them, which is
essential for the surviving of the organism as a whole. This could be wellpresented by the cell membrane, so in this lecture we will focus on
discussing the structure and function of the cell membrane before passing
toward the organelles and nucleus.
Structure of the cell membrane

Cell membrane is composed of lipid bi-layer with various proteins that are
embedded in. The lipid bi-layer isolates the cell from the extracellular
environment while the proteins give the membrane its specific functions.
Lipid bi-layer is actually formed by phospholipids.This due to the amphipathic
properties of the phospholipids. Phosphatidylcholine is the most abundant
phospholipid in the cell membrane.It is composed of hydrophilic polar
phosphate head, oriented toward the watery cytoplasm in on side of the
bilayer, and toward the extracellular fluid in the other layer, and of
hydrophobic tail, oriented toward the interior of the bilayer, which is water
free.
Other lipids in the cell membrane includes

Phosphatidylethanolamine: another phospholipid

Cholesterol, which is a steroid that gives the membrane its stability.

These various lipid components of the cell membrane give it its specific
feature as a semi-fluid structure.

Glycosphingolipids and sphingomyelin

Proteins of the cell membrane form about 50 % of its mass. They are subcategorized into two major groups:

Integral proteins: These proteins are located within the lipid bi-layer
and some of them pass though it ( transmembrane proteins) . They
span thickness of the membrane. They are amphipathic , and form
protein channels , protein carriers and receptors.

Peripheral proteins: They are located in the inner surface of the

membrane. They are polar, attached to integral proteins, and most of
them function as enzymes. G-Protein is an example of peripheral
protein too. Some of them function as anchor proteins, to which the
cytoskeleton is attached.

Glycoprotein: found on the cell surface and function as markers.

Distribution of proteins in cell membrane makes it asymmetrical.

Functions of cell membrane

In this lecture we will just underline the functions of cell membrane, then we
will discuss them in details during the next lectures.
1- Cell to cell adhesion, in order to form tissue.
2- Anchoring the cytoskeleton
3- Inercellular signaling, which facilitates communications between cells?
4- Transport: Cell membrane is semipermeable membrane, so it plays a very
important role in transport and controlling the entry of substances to cell and
exit out of it.
5- Enzyme activity: Cell membrane proteins catalyze some metabolic
processes near the inner cell membrane.
6. Cell recognition: by glycoprotein markers on the cell surface .

1. Cell- to- Cell Adhesion

Cell to cell adhesion is one of the functions of the cell membrane that
attaches cell to other cells or to the extracellular matrix in order to form
tissue .
Cell adhesion serves to structural and functional tasks.
Cell uses plasma membrane proteins to form different types of cell to cell
adhesion.
Before reviewing types of cell adhesion lets review the extracellular matrix
which is composed of non-cellular material that contributes to adhesion of
cells in the connective tissue especially.
Extracellular matrix is omposed of:

Polysaccharides: Polysaccharide of the ECM can be subdivided into

proteoglycan and non- proteoglycan polysaccharides .

Proteoglycans : ( Glucoseaminoglycans) : They are carbohydrate polymers

that are attached to protein fibers , and involve: Heparan Sulphate , Keratan
Sulphate , and chondroitin Sulphate .
Non-proteoglycan Polysaccharides : Hyaluronic acid

Protein fibers: Such as:

Collagen: the most abundant protein in the extracellular matrix and the most
abundant protein in the body as a whole as it forms about 90% of the bone
tissue. Collagen gives rigidity to tissues.
Elastin: It gives elasticity to tissues and allows them to be stretched and
recoiled, so it is found in organs like: skin, blood vessels and lungs.
Fibronectin : connects cells to collagen fibers and then facilitates the cell
movement.
Extracellular matrix also contains other components such as: growth
factors .It contributes to cell adhesion by binding the matrix to actin of the
cytoskeleton or to keratin filaments.

Clinical Physiology :

Rare disorders of fibers in extracellular matrix may causes diseases such as

cutis laxa , and William`s syndrome .
Briefly : Cutis laxa ( or dermatolysis) is a genetic disease that is caused by a
mutation in the elastic fibers of the dermis and is presented as inelastic skin
which is hang loosely in folds.
William`s syndrome is a genetic disease caused by partial deletion of
chromosome 7 and is presented with congenital malformations in skin and
cardiovascular system.
Types of Cell to cell adhesion:
Types of cell adhesion could be determined by the function that serves to. It
is formed by using cell membrane proteins:
1- Desmosome or Macula adherens (binding spot in Latin) is a type of
cell-to-cell adhesion that is found in tissues that are under continuous
physical stress such as heart and skin to prevent sharing of cells from each
others .It adheres two adjacent cells by binding the adhesive proteins that
belong to Cadherin family in the cell surface to the cytoskeleton leaving a
wide space between the two cells , which may reach 30 nm .
Cadherin is a family of adhesive integral protein that involves membrane
protein such as : desmoglein and desmocolin .
Each protein has an extra- and intra- cellular domain. The intracellular
domain is actually a thickened plaque which is formed of proteins like
plasmoplakin , and is connected to keratin fibers of cytoskeleton inside the
cell , while the extracellular domain is formed of the cadherin proteins.

Clinical Physiology: when desmosomes are damaged diseases result .

Examples :

Blistering diseases: A result of autoimmune damage of desmosome ,

leading to breakdown of cell adhesion in the skin and cause sharing of
epithelial layers of skin to get apart from each others and abnormal
fluid accumulation in these spaces.

Arrhythmogenic right ventricular cardiomyopathy : results from genetic

mutation in the desmosomes of the myocardium and causes a life
threatening situation due to disruption of normal rhythm of the heart .
Usually affects young athletes.

2- Tight Junction : or Zonula occludens is a type of cell adhesion that

tightly adhere two cells to form an impermeable to fluid passage barrier .
It is composed of cell membrane proteins ( claudin or occludin) that
extracellular domain of each of them is directly connected to other in the
adjacent cells to form sealing strands . The strand is then attached to
peripheral protein on the inner surface of the cell membrane, which anchor
the strand to the cytoskeleton.

The tightness of epithelial tissue is dependent on that whether tight junctions

are present or not so the epithelia could be classified as: tight epithelia (such
as distal and collected tubules of the kidney) and leaky epithelia (such as in
proximal tubules of the kidney). The tightness is much greater when the
strands are more numerous.

The adhesive (sealing) zones in the tight junction are also called (kissing
sites).
In addition to holding cells together, tight junction plays other roles such as:
controlling passage of substances through the spaces between cells, and so
protect delicate tissue (as in brain-blood- barrier). It also participates in
endo- and exo- cytosis by preventing movement of integral proteins from
one side to other of the cell membrane.
Blood brain barrier , which is composed of endothelial cells of brain
capillaries that are (tightly) adheses by tight junction form a barrier that
separate blood from brain extracellular fluid , so it forms a highly selective
barrier that prevent the delicate brain tissue from harmful substances ,
circulating in blood.
The space between the two adhesive cells is narrow in tight junction.

Clinical application:

Mutation in tight junction proteins may cause hereditary deafness

.Hereditary deafness is a result of Caludin 14 protein that form tight junction
strands. Hereditary hypomagnesemia is a hereditary disease, caused by
mutation in claudin 16.

3- Gap Junctions : in gap junction ( also called nexus ) the cytoplasm of two
adjacent cells is directly connected , allowing the passage of fluid , ions , and
other molecules in controllable manner. This will allow easy signal
transmition as in electrical synapses in the brain and cardiac cells.
Cell membrane proteins that form gap junctions are members of connexin
family of proteins. Each one is composed of a hemichannel (of connexin).
when the gap junction is composed of two identical hemichannels it is called
homotypic gap junction . When it is composed of two different hemichannel it
is called heterotypic.
Gap junction allows both electrical and chemical communication between
cells, so it is found much more in cardiac tissue, nerve tissue and retina. But
actually it is found in all types of tissue in our organism .

Clinical Physiology: Charcot-Marie- Tooth disease is a genetic disease due

to a mutation in connexin protein of nerve cells It causes motor and sensory
disorders as well as peroneal muscle atrophy.

Membrane transport
Membrane transport is a function of the cell membrane that enables
molecules and ions to enter in or leave the cell in order to survive.
Distribution of ions between the intra- and extracellular fluid is different. For
example Na+ has higher concentration in the ECF, compared to ICF, while
the concentration of K is higher inside the cell.
On the other hand Cl- concentration is higher in the ECF, while the phosphate
concentration is higher in the ICF. We also have to remember that negatively
charged intracellular proteins do not cross the cell membrane and always
stay inside. This arrangement is necessary to regulate movement of water
and electrolytes in both side to enable cell to survive.

As we know, cell membrane is composed of lipid bi-layer that is impermeable

to polar materials and embedded proteins that form channels and carriers.
Lipid bi-layer separates intra- and extra- cellular compartments, while
transport of molecules and ions usually occur via the membrane proteins.
This gives the plasma membrane its characteristic feature as selective semipermeable membrane.
Membrane transport has the following major forms:

I- Passive transport : Involves membrane transport that allows movement

of substances down their concentration gradient. It does not use energy in
form of ATP (But always use energy in other forms, mainly: kinetic energy of
molecules)

1- Simple diffusion: It simply means random movement of molecules

between two compartments where there is a concentration gradient for a
given molecule (the concentration of a molecule is higher in one sides than
the concentration of the same molecule on the other side). The molecules in
simple diffusion move DOWN a concentration gradient (from higher
concentration to lower concentration), for this random movement they use
the kinetic energy, stored in each molecule. Diffusion will continue until
concentration in both sides becomes equal.

Keeping in mind that concentration difference is a dynamic process, so we

have to expect that diffusion would never stop except at 0 Kelvin
temperatures.
The rate of diffusion depends on many factors:
a. The concentration difference: When concentration difference increases,
the diffusion rate increases.
b. The pressure difference on both sides of the membrane. When it is
increased the diffusion rate increases.
c- Surface area: the rate increases when the surface area increases.
b- The distance between the two compartments: the rate decreases when
the distance increases.
c- Temperature: the rate increases when the temperature increases.
e- Molecular weight: when the molecular weight is larger the diffusion rate is
slower.
f- Electrical potential: When the charge of one side is different, the diffusion
of differently charged ions will be increased even the concentration
difference does not exist.

Small hydrophobic molecules such as gases can diffuse easily in and out the
cell, due to the fact that lipid bi-layer is permeable to them. Water is polar
but it can cross the membrane due to its small molecules via protein
channels.

2- Facilitated diffusion: Facilitated diffusion is used to transport large

molecules such as glucose and amino acids, because they are either large or
polar they cannot cross the lipid bi-layer, instead they use the membrane
protein carriers. So this is the difference between simple and facilitated
diffusion: diffusion here is passive too and occurs down concentration
gradient, but it occurs via protein carriers, and not through the phospholipids
of the lipid bi-layer. This type of transport is also passive and does not need
energy in form of ATP.
Facilitated diffusion is different from simple diffusion due to what is known as
transport maximum (V max). This maximum limits the transport when the
concentration increases. This occurs because the carrier protein to be able to
transport a substance it has to change its shape (conformational change),
thus it needs time to return to its original shape, which allows it to transport
new particles, in addition to the limited number of the carriers in the cell
membrane.

II- Active transport: This type of transport needs energy in form of ATP to
pump molecules AGAINST their concentration gradient (from lower
concentration to higher concentration of molecules) by protein pumps, such
as Na/K pump, or calcium pump or Na/ H pump...etc. These proteins are
called transporters.
Active transport is very specific, which means that it allows the cell to select
substances taken up.
As we mentioned, this type of transport needs energy in form of ATP
.Knowing that we use more than one third of our metabolic energy for active
transport, we can understand the importance of this transport for our
homeostasis.

One of the properties of active transport is that it reaches a transport

maximum when all its transporters are occupied (saturated) by the
molecules. This is a very important physiologic property.
Active transport has three forms:

1- Primary active transport: when the energy is used just for transport of
molecules UP concentration gradient, using ATP hydrolysis as a source of
energy. Na/K pump is the best example. The pump is found in the basolateral
membrane of the epithelial cells. It transport 3 Na+ out of the cells and 2 K+
into the cell and thus creates sodium concentration gradient.
2- Secondary active transport: This type of transport combines active
transport and facilitated diffusion. For example: Na pump produce
concentration gradient by active transport, which would be used for
transport of sugar or amino acid (facilitated diffusion). In such case ATP is
used to create Na concentration gradient and would not be used directly by
glucose or amino acid.
When two molecules are transported in the same direction, the transporter is
called symporter or co-transporter.
When the two molecules are transported in two different direction, the
transporter is called antiport , or contra-transporter
Examples:

* Na/K contratransport
* Na/H contratranspot ( in the parietal cells of the stomach)
* Na/K/2Cl cotransport ( in the ascending limb of loop of Henle)
* Na/Glucose ( In the proximal tubule of the kidney and the intestinal cells).

.3- Bulk transport: We mean by bulk transport merging of the plasma

membrane with a vesicle to enforce content of the vesicle to get in or out the
cell. This type of transport needs energy in form of ATP. It is regulated by
vesicle transmembrane protein in the plasma membrane, and could be
subdivided into:
a- Exocytosis: expelling substances out of the cell. This type of transport is
used to transport protein out of cells via two pathways:

Nonconstitutive pathway: Transport of protein inside secretory granules

from Goldgi`s apparatus for further processing before expelling them
out of the cell.

Constitutive transport: Transport of protein in vesicles without storage

or
b- Endocytosis : entering substances into the cell.

Both of the above mentioned subdivision could be also subdivided into:

i- Phagocytosis: This means transport of solid

ii- Pinocytosis ; which means transport of liquid .

Intercellular signaling
By: Dr.Abdulrahman A. Aqra MD MSc
Cells of our multicellular organism work collectively to maintain balanced
internal environment (homeostasis) , protect the organism from foreign
invaders ( immunity) , grow, develop, coordinate metabolism, and do many
other tasks.
To accomplish these complicated tasks, cells need to communicate with each
others, and they do that through what is known as intercellular signaling. The
mentioned signaling systems also enable cells to respond to changes in the
external environment and react to.
When intercellular signals are correct, the status of the organism is healthy
and physiologic. But when there are error signals, different and numerous
diseases such as autoimmune (Lupus erythematosis for example), metabolic
(diabetes mellitus) , and neoplastic diseases ( cancer ) will appear .

Intercellular signaling is a complex system, which involves many cellular

structures that either form a signal or respond to it. In general line, the
signaling system has the following elements:

Signal producing cell: a cell that is able to synthesize and release a

signal substance.
Signaling substance (ligand): produced and released by signaling cell,
and could be a neurotransmitter, hormone, immune modulator, ion or
other endogenous biologically active chemicals.
Target cell: a cell that receives the signaling substance via a receptor,
and switch on signaling pathway within it to process a response.

How do cells intersignal (communicate)

Cells communicate with each others either:

Directly (through gap junctions for example): Some neurons in the

central nervous system and the cardiac muscle cells and some smooth
muscle cells communicate in this way.
By chemical substances , produced by signaling cell and bind to
receptors of other target cells :Most cells of our organism communicate
by this way. Signaling substances could be hormones (insulin for
example), cytokines, drugs, toxins or others.
Receptors are molecules that usually found on the surface of the cell or
inside it, they receive cellular signals through binding with a ligand and
the result of this binding is ordering the cell to (do) something such as :
allowing some molecules to get inside ( ions for example) or cell
division , or producing cellular protein ...etc.
Receptors could be classified as surface receptors (cell membrane),
cytoplasm receptors, or nuclear receptors. The later two are also called
intracellular receptors. The peptide hormones like insulin bind to
surface (membrane) receptors, while steroid hormones like aldosterone
bind to intracellular receptors.
After binding of ligand with the receptor they form what is known as
ligand - receptor complex which will start series of biochemical reaction
inside the cell, either directly or through a second messenger system .

Types of intercellular signaling

There are many types of intercellular signaling , depending on the function of
each type :
1- Intracrine : when signals are produced and function within the cell itself
Usually, Intracrine signaling is considered as a part of intracellular signaling
pathway that is switched on after receiving a signal from other cell (external
trigger).

2- Autocrine: when a given cell produces and releases a ligand, the ligand
after being released it would bind to a receptor on the cell membrane of the
cell itself to cause a signal inside it. This usually occurs in T-lymphocytes.
Another good example is Interleukin-1 in monocytes because they bind to
receptors on the cell surface of the same cells and produce signals after
being stimulated by external stimulus.
3- Juxtacrine: When signaling occur through direct contact with the adjacent
cells via the components of the cell membrane (usually via cell membrane
proteins, each of which has intra-and extracellular domain. When the
extracellular domain binds to each other, this will initiate a signal in the
target cell. This type of signaling is of importance in embryological cells.
4- Paracrine: When emitting cells send signals to the vicinity (such as signals
done by neurotransmitters in chemical synapses in nervous system).
5- Endocrine: when the cell produce a signal that affect signal cells, usually
via peripheral bloodstream ( such as hormones).
Intracellular signaling
The receptor recognizes the signal and then an intracellular chain of reaction
occurs to achieve a cellular response, such as: muscle contraction, nerve
excitation or inhibition, increase protein synthesis, cell division, and
apoptosis Etc.

Types of receptors:
I. Cell surface receptors: integral proteins in the cell membrane that span it
with a part outside the cell membrane that bind to the ligand and another
part inside the cell which transmit an effect, either by opening ion channels,
which are directly connected to the receptor (ionotropic receptors) or usually
via a second messenger (metabotropic receptor).
The receptor binds only a specific ligand..

There are many second messenger systems in the cells, but the major well
known system are three:
1. Ca+ ions : On which many vital processes depend, such as
neurotransmition, contraction of skeletal, cardiac, and smooth muscles, and
others. Calcium ions bind intracellular proteins and activate them, such as:
actin and myosin in skeletal and cardiac muscles, calmodulin in smooth
muscles, and SNARE proteins in nerve cells.
2. G- cyclic AMP system: a ligand binds to a specific cell surface receptor,
this complex activates adenylyl cyclase, the later will convert ATP into cAMP,
which is necessary for activating protein kinase A. The later then causes
activation of intracellular enzymes by phosphorylation.
3. The phosphatidylinositol triphosphate IP3 : It mobilizes calcium ions from
intra- and extracellular resources.
II. Intracellular receptors, that are soluble proteins found in the receptive
areas of cytoplasm or the nucleus. It binds the lipophilic ligands that can
cross the cell membrane
In the auditorium we give many example. So please read them from your
notes.