Cell signaling / Signal Transduction / Transmembrane signaling. It is the process by which cells communicate with their environment and respond to external stimuli. When a signaling molecule(ligand) binds to its receptor, it alters the shape or activity of the receptor, triggering a change inside of the cell such as alteration in the activity of a gene / cell division. Thus the original Intercellular Signal is converted into an Intracellular Signal that triggers as a response.

1. CELL SIGNALING
Pavana K A
M.Pharm, 1st sem, Pharmacology
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2. CONTENTS
 Introduction
 Types of signaling pathways
 Types of receptors
 G-Protein coupled Receptors
 Tyrosine kinase receptors
 Secondary messengers
 Intracellular signaling pathways
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3. INTRODUCTION
 Cell signaling / Signal Transduction / Transmembrane signaling.
 It is the process by which cells communicate with their environment
and respond to external stimuli.
 When a signaling molecule(ligand) binds to its receptor, it alters the
shape or activity of the receptor, triggering a change inside of the cell
such as alteration in the activity of a gene / cell division. Thus the
original Intercellular Signal is converted into an Intracellular Signal
that triggers as a response.
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4. TYPES OF SIGNALING PATHWAYS
 Cells communicate by means of extracellular signaling molecules that
are produced and released by signaling cells. These molecules
recognize and bind to receptors on the surface of target cells where
they cause a cellular response by means of a signal transduction
pathway.
1. Endocrine signaling: Secrets hormones into the bloodstream that
are distributed widely throughout the body. Many of the same types
of signaling molecules are used in paracrine, synaptic signaling.
The difference lies in the speed and selectivity with which the
signals are delivered to their targets.
2. Synaptic Signaling: Neurons transmit signals electrically along
their axons and release neurotransmitters at synapses.
3. Paracrine Signaling: Signals that are released into the
extracellular space and act locally on neighboring cells.
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5. TYPES OF RECEPTORS
There are number of receptor classes that are used in different
signaling pathways.
 Ligand gated ion channels.
 G-protein couples receptors.
 Tyrosine kinase receptors.
 Nuclear Receptors.
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6. G-PROTEIN COUPLED RECEPTORS
 These are a large family of cell membrane receptors. It consists of
single polypeptide chain, their characteristic molecule has 7α Helical
membrane spanning hydrophobic amino acids segments.
 Agonist Binding site is located between the helicals of extracellular
domain.
 3 subunits – α, β, γ(gamma)
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8. TYPES OF G-PROTEIN RECEPTORS
 GS : Adenylyl Cyclase Pathway Activation
 Gi : Adenylyl Cyclase Pathway Inhibition
 Go : Ca2+ Channel Inhibition
 Gq : Phospholipase C Activation
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Major Effector Pathways
1. Adenylyl Cyclase / cAMP Pathway
2. Phospholipase C / IP3-DAG Pathway
3. Ion Channel Regulation.

9. ADENYLYL CYCLASE PATHWAY
 Activated By Gs Receptor Activation.
 Increases the Intracellular Accumulation of Second messenger
cAMP Activates Protein Kinase A
Phosphorylates other Enzymes, Alters the function of ion channels,
Transporters which leads to increased Contraction, Impulse
generation in heart, Smooth Muscle relaxation, Glycogenolysis,
lipolysis etc.,
 cAMP directly opens membrane Ca2+ Channels found in Heart,
kidney and Brain thus increases Intracellular Ca2+ levels leads to
contraction.
 Opposite effects are Produced when Adenylyl Cyclase Is
Inhibited(Gi)
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10. PHOSPHOLIPASE C PATHWAY
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11. ION CHANNEL REGULATION
 The activated G Proteins(Gi ,Go , Gs ) can also open or inhibit Ionic
channels specific for Ca2+ and K+ , without involving any second
messengers like cAMP or IP3 and leads to Hyperpolarization and
depolarization.
 Gs : Opens Ca2+ Channels in myocardium and skeletal muscles.
 Gi and Go : Opens K+ Channels in heart and smooth muscles.
 These Functions are Caused by the Action of βγ Complex/ dimer.
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12. TYROSINE KINASE RECEPTORS
 It consists of a protein That may form dimers or multisubunit
complexes, Upon activation they undergo Conformational
Changes resulting in Increased Cytosolic enzyme activity
depending on their structure and function.
 This response lasts for minutes to hours.
 The activated receptor phosphorylates Tyrosine residues on
itself and the other specific proteins.
 Activates kinase to auto phosphorylate tyrosine residues on
each other increasing their affinity for binding substrate
proteins which have SH2 domains
 These are then phosphorylated and released to carry forward
the cascade of phosphorylation's leading to the response.
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13. SECONDARY MESSENGERS
 They act as links(transducers) in the communication between
the neurotransmitter and the action generated within the
effector cell.
 Cyclic AMP
 Cyclic GMP
 Calcium Ion
 Inositol 1,4,5-Triphosphate(IP3)
 Nitrous oxide(NO)
 Diacyl Glycerol
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14. CYCLIC AMP
 Synthesized from ATP by Adenylate cyclase.
 Activated by Adenylyl Cyclase stimulatory G (Gs)PCR, and Inhibited By
Inhibitory G(Gi)PCRs.
 Intracellular signal transduction, the effects of hormones like Glucagon
and Adrenaline into the cell which cannot pass through the plasma
membrane.
 Activation of Protein Kinases.
 Binds to and regulates the function of Ion Channels such as
HCN(Hyperpolarization-activated Cyclic Nucleotide-gated channels)
and few cyclic nucleotide binding proteins(Epac1 and RAPGEF2)
 cAMP and its associated kinases functions in regulation of metabolism
of Glycogen, sugar and lipids.
 Lac Operon, at low glucose cAMP accumulates and binds to the
allosteric site on CRP. RNA polymerase binds to adjacent promoter to
start transcription of the lac operon.
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15. CYCLIC GMP
 Guanylate cyclase catalyzes cGMP synthesis From GTP.
 Activates intracellular protein kinases in response to the binding of
Membrane impermeable Peptide hormones.
 Regulates ion channel conduction, glycogenolysis, cellular Apoptosis,
Relaxes smooth muscle tissues-Vasodilation-Increased Blood flow.
 SM in Photo transduction in the eye. (Light: Activates PDE : Degradation
of cGMP : Closes Sodium channels : Hyperpolarization of Photoreceptor
PM : send visual info to the brain.)
 Activates Protein Kinase G.
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16. INOSITOL 1, 4, 5-TRIPHOSPHATE
 Activation of Phospholipase C (Gq) releases secondary messengers
IP3 and DAG , IP3 is obtained by the Hydrolysis of PIP2.
 IP3 is soluble and diffuses through the cell cytoplasm to the ER Or
SR (muscle cells) , Binds to the IP3 Rc on a ligand gated Ca2+
Channel on the surface of ER. It triggers the opening of Ca2+
Channel and releases Ca2+ into the cytoplasm. In heart muscle cells
increased Ca2+ Activates the Ryanodine Receptor Operated channel
on the SR , Results in further increase in Ca2+ which leads to
contractions.
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17. DIACYL GLYCEROL
 It is a glyceride consisting of two fatty acid chains covalently
bonded to a glycerol molecule through ester linkages.
 Phospholipase C activation releases IP3 and DAG.
 DAG remains within the plasma membrane due to its hydrophobic
Properties.
 Activates Protein Kinase C.
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18. NITRIC OXIDE
 NO is produced by the action of nitric oxide synthase, an
enzyme that converts Arginine into metabolite citrulline and
simultaneously generates NO.
 The nitric oxide synthase is regulated by calcium binding to
Calmodulin.
 Activates Guanylyl cyclase which increases the cGMP levels
and thereby lowering Ca2+ levels.
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19. INTRACELLULAR SIGNALING PATHWAYS
 Cyclic AMP signaling Pathway.
 Mitogen Activated protein kinase ( MAPK) signaling pathway.
 Janus kinase(JAK) / Signal Transducer and Activator of
transcription( STAT) signaling pathway.
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20. MAP KINASE SIGNALING PATHWAY
 Activated By Growth factors and Cytokines acting on Kinase
linked receptors and also By GPCR.
 It controls many processes involved in Cell division, Apoptosis
and Tissue Regeneration.
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The protein kinase that catalyzes both threonine and tyrosine
phosphorylation is called as MAP kinase-kinase.
MAP-kinase-kinase-kinase is often a serine/threonine kinase called Raf which
gets activated by binding of Activated Ras.

22. JAK/STAT PATHWAY
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24. REFERENCES
 Lippincott Illustrated Reviews: Pharmacology Sixth Edition
 Rang and Dale’s Pharmacology, Seventh Edition
 Alberts-Molecular Biology of the cell.
 Essentials of Medical Pharmacology- K D Tripathi, SixthEdition
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