Cell signaling is a complex communication system that regulates cellular activities and is critical for development, immunity, and tissue repair, with dysfunctions leading to diseases such as cancer and diabetes. The process involves various mechanisms including direct contact between cells and the use of signaling molecules that bind to receptors, triggering cellular responses through pathways like GPCRs and receptor tyrosine kinases. Understanding these pathways can improve disease treatment and facilitate the creation of artificial tissues.

1. CELL SIGNALING
BY
Ved prakash panda
M. Pharm
Pharmacology

2. Cell signaling
 is part of a complex system of communication that
governs basic cellular activities and coordinates cell
actions. The ability of cells to perceive and correctly
respond to their microenvironment is the basis of
development, tissue repair, and immunity as well as
normal tissue homeostasis. Errors in cellular
information processing are responsible
for diseases such as cancer, autoimmunity,
and diabetes. By understanding cell signaling,
diseases may be treated effectively and, theoretically,
artificial tissues may be created.

4. MECHANISM: Cell signaling done by two
mechanisms: 1) some cell-to-cell communication
requires direct cell-cell contact
2) some cells can form gap junctions
that connect their cytoplasm to the cytoplasm of
adjacent cells (eg:cardiac muscle).
The notch signaling mechanism is an example of
juxtacrine signaling (also known as contact-
dependent signaling)in which two adjacent cells
must make physical contact in order to
communicate.

5.  Signaling molecules are synthesized by signaling cells and
produce a specific response only on target cells that have
receptors for signaling molecules(eg:steroids ,thyroxin).
 Signaling molecule acts as a ligand ,which are recognize and
binds to receptor causes a conformational change in the
cytosolic domains of the receptor that induces specific
cellular responses.
 The process of converting signals into cellular responses, as
well as the individual steps in this process, is termed signal
transduction.
 Transduction pathways may involve few r many components.
 Signaling pathways commonly based on the general classes of
receptors involved (e.g;GPCRs,tyrosine kinases),the type of
ligand.

6. Types of signaling
3types of signaling :
ENDOCRINE :hormones are produced by an
endocrine gland nd sent through the blood stream
to distant cells. Eg;TSH,progesterone,testosterone.
PARACRINE :signaling molecule affects nly target
cells in the proximity of the signaling cell.Eg:musle
contraction.
AUTOCRINE:In this cells respond to molecules they
produce themselves.Eg:growth factors
,prostaglandines.

7. RECEPTOR
 DEFFINITION;
 Many drugs act by binding to specific protein
macromolecules in the cell membrane are in the
cytosol, and regulate the cell function by altering
enzyme activity ,permeabilty to ions conformational
features are genetic material in the nucleus , such
protein macromolecules with functional correlates
are called “Receptor”.

8. Types of Receptors
1. Ion channel receptors.
2. G protein-coupled receptors.
3. Tyrosine kinase receptors.
4. Nuclear receptors
G protein-coupled receptors:
 Receptor - G protein- lipid in cell membrane.
 Ligand - receptor - G protein – effector enzyme to
generate an intracellular second
messengers(intracellular signal transduction).
 GPCRs contains 7 membrane-spanning regions with
their N-terminus n the exoplasmic face nd C- terminus
n the cytosolic face .

9. ACTIVATION OF G-PROTEIN BY RECEPTOR
 Ligand
Exchange in the alpha sub unit,switching it to the activated state.
 G-proteins consists of 3 sub units:alpha,beta ,gamma
 Guanine nucleotides bind to alpha subunit,which have enzymatic activity
,catalyzing the conversion of GTP to GDP.
 The beta nd gamma subunits remain together as a beta gamma complex.
 In the resting state ,G-protein existing as an unattached
Alpha beta gamma trimer.
 When GPCR is activated by agonist molecule,conformational change occurs
in receptor.
 Association of alpha beta gamma with receptor causes the bound
GDP to dissociate nd to be replaced with GTP,which causes dissociation of the
G-protein trimer,releasing alpha-GTP nd beta gamma subunits;these r active
forms of G-protein, which diffuse in the membrane and can associate with
various enzymes causing activation of the target.
recept0r G-protein GDP-GTP

11.  Association of alpha subunits with target enzyme can cause
either activation r inhibition ,depends on wch G-protein in
involved.
 Signaling is terminated when the hydrolysis of GTP to GDP
occurs through the GTPase activity of alpha subunit.
 Resulting alpha-GDP then dissociate from the effector, and
reunits with beta gamma,completing the cycle.
 A single agonist-receptor complex can activate several G-
protein molecules in turn,nd each of these can remain
associated with the effector enzyme for long enough to
produce many molecules of product.
 The product is called “second messenger” nd further
amplification occurs before the final cellular response is
produced .

12. KINASE- LINKED RECEPTORS
Receptors for various growth factors incorporates
tyrosine kinase in their intracellular domain.
Cytokine receptors have an intracellular domain
that binds and activates cytosolic kinases when the
receptor is occupied.
Protein phosphorylation and kinase
cascade mechanisms:
Phosphorylation and dephosphorylation are
accomplished by kinases and phosphatases.
Ligand binding to receptor leads to dimerisation.

13. The association of the two intracellular kinase
domains allows a mutual autophosphorylation of
tyrosine residues.
The phosphorylated tyrosine residues then serve as
high-affinity docking sites for the proteins.
One important group of such “adopter proteins” is
knows as the “SH2 domain proteins”which r allowing
control of many cell functions.
These forming a recognition site for the
phosphotyrosine residues of the receptor.

14. Ras/Raf pathway
 They are involved mainly in events controlling cell growth and
differentiation,and act indirectly by regulating gene transcription.
 Two important pathways are:
The Ras/Raf/mitogen-activated protein(MAP) kinase pathway,(
which is important in cell division,growth and differentiation) .
 Ras which is a proto-oncogene product,conveys the signals from
the SH2domain protein,Grab,which is phosphorylated by the
RTK.
 Activation of Ras in turn activates the Raf ,which is the 1st of a
sequence of 3 serine /threonine kinases,each of which
phosphorylates, nd activates the next in line.
 The last of these MAP kinase , phosphorylates one or more
transcription factors that initiates gene expression, resulting in a
variety of cellular responses, including cell division.

16. Jak/stat pathway
Jak/stat pathway is involved in responses to many
cytokines.
Dimerisation of these receptors occurs when
cytokine binds,nd this attracts a cytosolic tyrosin
kinase unit(jak) to associate with, nd phosphorylate,
the receptor dimer.
Jak belong to a family of proteins, different members
having specificity for different cytokine receptors.
The targets for phosphorylation by Jak are a family
of transcription factors(stats)

18. The targets for phosphorylation by jak are a family of
transcription factors(stats).
These are SH2 domain proteins that binds to the
phosphotyrosine groups on the receptor-Jak
complex ,and are themselves phosphorylated. Thus
activated ,Stat migrates to the nucleus and activates
the gene expression.

19. INTRACELLULAR SIGNAL TRANSDUCTION
 Various intracellular pathways that transduce signals
CARRY SIGNALS FROM MANY RECEPTOSECOND MESSENGERS :
 The binding of ligands(“1st messengers”) to many cell surface
receptors leads to a short-lived increase r decrease in the con of
certain low-molecular-weight intracellular signaling molecules
termed “second messengers”.
 These molecules include 3’ ,5’-cyclic AMP(cAMP) ,3’,5’cyclic
GMP(cGMP), 1,2-diacylglycerol(DAG),inositol 1,4,5
triphosphate(IP3),
 Other important secondary messengers are Ca2+ and various
inositol phospholipids, also called phosphoinositides,which
embedded in cellular membranes.

20. The adenylyl cyclase / cAMP
 Cyclic 3’,5’-adenosine monophosphate is a nucleotide
synthesized within the cell from ATP by the action of
enzyme adenylyl cyclase.
 cAMP inactivated by hydrolysis to 5’-AMP,by the action
of a family of enzymes known as phosphodiesterases.
 cAMP regulates many cellular functions
including,eg:enzymes involved in energy metabolism,cell
division, ion transport etc.
 These effects are brought about by a common
mechanism is activation of protein kinases by cyclic
AMP.
 Protein kinases regulate the function of cellular proteins
by controlling protein phosphorylation.

21.  Eg: cyclic AMP
Cyclic AMP dependent protein kinases increase
phosphorylation of voltage-activated calcium channels
increase the amount of Ca+2 entering the cell during
action potential, - increasing the force of contraction of
heart.
 In smooth muscle, cyclic AMP-dependent protein kinase
phosphorylates the another enzyme, myosin-light-chain
kinase,wch is required for contraction .
 The smooth muscle relaxation produced by many drugs
that increase cAMP production in smooth muscle.
Ca2+ Contraction of muscle

22. Adenylate
cyclase
ATP
cAMP
Protein kinase
(inactive)
Protein kinase
(active)
Lipase
(inactive) ATP
ADP
Lipase (active)
Glycogen synthase
(active)
Glycogen synthase
(inactive)
ATP
ADP
Increased
lipolysis
Reduced glycogen
synthesis

23. Adenylate
cyclase
ATP
cAMP
Protein kinase
(inactive)
Protein kinase
(active)
Phosphorylase
Kinase(inactive)
Phosphorylase
Kinase(active)
ATP
ADP
Phosphorylase b
(inactive)
Phosphorylase a
(active)
ATP ADP
Glucose1-
phosphate
ATP ADP
Increased glycogen breakdown
Glycogen

24. The phospholipase C/inositol phosphate system
Membrane bound phosphorylated inositol lipids,
collectively referred to as phosphoinositides.
The mechanism of nasal gland secretion was
accompanied by increased by PI.
Many hormones that produce an increase in free
intracellular Ca2+ con also increase PI turnover.
Phosphatidylinositol 4,5 biphosphate( PIP2) is the
substrate for a membrane-bound enzyme,
phospholipase ,wch splits into DAG nd IP3)( inositol
1,4,5 tri phosphate).

25. Inositol phosphates and intracellular calcium
IP3: inositol tri phosphate is a water soluble mediator
that is released into the cytosol nd acts n a specific
receptor-the IP3 receptor- wch is a ligand gated
calcium channel present in the membrane of the
endoplasmic reticulam .
The main role of this is to control the release of
Ca2+ from introcellular stores.
IP3 is converted into IP4,by specific kinase.the exact
role of IP4 is unclear, but there is evidence that it
too is involved in Ca2+ signaling.

26. Diacylglycerol and protein kinase C
 The main effect of DAG is to activate membrane-bound
protein kinase ,protein kinase C , which catalyses the
phosphorylation of intracellular proteins.
 DAG is highly lipophilic in nature. It binds to a specific
site on the PKC molecule,wch migrates from cytosol to
cell membrane .
 DAG mainly involved in increasing intracellular Ca2+.
 One of the subtypes is activated by the arachidonic acid
generated by the action of phospholipase A2 and the
membrane phospholipids.
 PKC activation can also occur with agonists that activate
this enzyme.