Cell signaling

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 , 1 st sem , Pharmacology 1

2. CONTENTS Introduction Types of signaling pathways Types of receptors G-Protein coupled Receptors Tyrosine kinase receptors Secondary messengers Intracellular signaling pathways 2

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. 3

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 . 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. Synaptic Signaling: Neurons transmit signals electrically along their axons and release neurotransmitters at synapses. Paracrine Signaling: Signals that are released into the extracellular space and act locally on neighboring cells. 4

5. Types Of Receptors T here 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. 5

6. G-Protein Coupled Receptors These are a large family of cell membrane receptors. It consists of single polypeptide chain, their characteristic molecule has 7 α Helical membrane spanning hydrophobic amino acids segments. Agonist Binding site is located between the helicals of extracellular domain. 3 subunits – α , β , γ (gamma) 6

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8. Types of G-Protein Receptors G S : Adenylyl Cyclase Pathway Activation G i : Adenylyl Cyclase Pathway Inhibition G o : Ca 2+ Channel Inhibition G q : Phospholipase C Activation 8 Major Effector Pathways Adenylyl Cyclase / cAMP Pathway Phospholipase C / IP3-DAG Pathway 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 Ca 2+ Channels found in Heart, kidney and Brain thus increases Intracellular Ca 2+ levels leads to contraction. Opposite effects are Produced when Adenylyl Cyclase Is Inhibited(Gi) 9

10. Phospholipase C Pathway 10

11. Ion Channel Regulation The activated G Proteins(Gi ,Go , Gs ) can also open or inhibit Ionic channels specific for Ca 2+ and K + , without involving any second messengers like cAMP or IP 3 and leads to Hyperpolarization and depolarization. Gs : Opens Ca 2 + 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. 11

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. 12

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 13

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. 14

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. 15

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 Ca 2+ Channel on the surface of ER. It triggers the opening of Ca 2+ Channel and releases Ca 2+ into the cytoplasm. In heart muscle cells increased Ca 2+ Activates the Ryanodine Receptor Operated channel on the SR , Results in further increase in Ca 2 + which leads to contractions. 16

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. 17

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 Ca 2 + levels. 18

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. 19

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. 20

21. 21 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 22

23. 23 THANK YOU

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 24