2. By the end of this lecture you will be able to :  Classify receptors into their main superfamilies  Identify the nature & time frame of their response  Recognize their different transduction mechanism ilo s

3. 1. Recognition 2. Reception 3. Transduction 4. Response A RECEPTOR  Coupler  Transduction Direct  Its Structure: 1 2 3 4

4. Location Structure Transduction Mechanism Classified according to their Time scale of Response  4 Main SUPERFAMILIES Channel-Linked Receptor G-Protein Coupled Receptors Nuclear Receptors Enzyme-Linked Receptors Nature of Response

5. Channel-Linked Receptor 1 Ionotropic Receptor Ligand-Gated-Ion Channel Involved in fast synaptic neurotransmittion occuring over milliseconds It is activated directly when a ligand comes to bind to receptors that are incorporated as part of its structure Examples; Nicotinic Ach receptor activated by Ach

6. Different from Voltage-Gated Ion Channel Different from Voltage-Gated Ion Channel That is activated by a change in action potential Not by occupancy of a ligand

7. G- Protein G-Protein-Coupled Receptor Metabotropic Receptor  PHOSPHORYLATION OF TARGET PROTEINS Involved in less rapid transmission of Transmitters: Adrenaline at Adr R, Ach at mAch R …etc Hormones; Glucagon Others; Peptides, Purines, …etc An enzyme coupled to a  2nd messenger    RESPONSE Go-between proteins Coupler Agonist 2 1. Agonist occupancy dissociates [  ], replaces GDP by GTP, activates effector 2. Agonist loss cleaves GTP by GTPase binds [    ] again and GDP Composed of 3 subunits [    ] & GDP  G-Protein 1. Adenyl cyclase (AC)  cAMP  PKA 2. Phospholipase C (PLC)  IP 3  Ca ++ intacellular Ca 2+ /CaM  CAMPK  DAG  PKC

8.    ATP G-Protein 3 subunits [    ]  + GDP R E PKA G-Protein-Coupled Receptor Adenyle cyclase

9.    ATP R E cAMP PKA P P P Channels Enzymes Cytoskeletal Proteins  

10.    E Phospholipase C  PIP 2 DAG  Phosphatidic a Inositol ↑ G-Protein-Coupled Receptor IP 3 Ca ++ PKC +CaM Cytoskeletal Proteins Channels P P CAMPK P P Enzymes  P

11. Different in G-Protein Classes Divided according to their α-subunits into G s, G i and G q G s and G i produce, respective, stimulation and inhibition of AC G q is linked to activation of PLC-IP 3 -Ca ++ CaM & PKC Receptors are selective to  subunit & effector with which they couple

12. a 1 Adrenoceptors couple to G q to stimulate PLC.  2 Adrenoceptors couple to G i to inhibit AC.  1&2 Adrenoceptors couple to G s to stimulate AC ADRENOCEPTORS + + AC  Adrenoceptor  2 Adrenoceptor Inhibitory ReceptorStimulatory Receptor Adr GsGs GiGi ↑ cAMP  cAMP Adr

13. M 1 & M 3 Ach receptors couple to G q to stimulate PLC M 2 & M 4 Ach receptors couple to G i to inhibit AC CHOLINERGIC RECEPTORS + + + + PLC GqGq GqGq BronchiBlood Vessel PLC   Adrenoceptor M 3 Ach receptor Stimulatory Receptor ↑ Ca ++ Adr Ach ↑ Ca ++

14. Enzyme-Linked Receptors 3 Involved in slow action of; hormones (insulin), growth factors, cytokines, ….. Their cytosolic domain either: 1.Associate directly with an enzyme GC (guanyl cyclase) as in ANP receptor. 2. Possess intrinsic kinase activity (as tyrosine or serine/threonine kinase) that can phosphorylate itself (autophosphorylation) & / or other proteins that they dock as in insulin receptor They control many cellular functions as motility, growth, different- iation, division & morphogenesis. This usually require many intracellular signaling steps that take time to process.

15. Enzyme-Linked Receptors 3 1.Guanyle cyclase-Linked Receptors They have a single transmembrane spanning element. These have integral intrinsic guanylate cyclase activity. Their 2 nd messenger is cGMP → activates PKG → phosphorylate down stream protein signaling molecules. ↑ cGMP Example: Atrial Natriueretic Peptide [ANP] receptors

16. Phosphorylate other proteins that it docks Activated Receptor autophosphorylates Ligands dimerize receptors Tyrosine Kinase-Linked Receptors Enzyme-Linked Receptors 3 Phosphorylated docked proteins RESPONSE Example Insulin receptor

17. Nuclear Receptors 4 Are intra-cellularly located whether in cytosol or the nucleus. Their ligands are usually : Extracellular lipophylic hormones; steroids, thyroids, …etc Extracellular lipids; linolinic a., retinoic a. Phosphorylated protein end product of 2 nd messenger signaling Protein Transcription Translation  Involved in regulation of PROTEIN SYNTHESIS → most slowest in action.  They possess a conserved area that recognizes specific DNA sequence in the nucleus which is called a Responsive Element  They react as TRANSCRIPTION FACTORS expressing or repressing target genes.

18. proteins Nuclear Receptors 4 The activated GR complex  Up-regulates expression of anti- inflammatory proteins  Represses expression of pro-inflammatory proteins in cytosol ( preventing the translocation of other transcription factors from the cytosol into the nucleus). GLUCOCORTICOID RECEPTOR

19. THYROID HORMONE RECEPTOR THYROID HORMONE RECEPTOR Nuclear Receptors 4

20. ConductanceCell Signal  Transcription & Translation Cell Signal    Hours / Days Minutes / Hours 1234

21. mAch; m 1, m 2, m 3, m 4, Adrenergic receptors;          5-HT 1; 5-HT 1A – 1D receptor G-Protein-Coupled Receptor Different Classes of Receptors Different Receptors Subtypes Ach R  m Adrenergic R   &  Dopaminergic R  D 1 & D 2 5-HT  5-HT 1-2 / 5-HT 4-7 Different in G-Protein Classes Are the Most Abundant Type Divided according to their α-subunits into G s, G i and G q G s and G i produce, respective, stimulation and inhibition of AC G q is linked to activation of PLC-IP 3 -Ca ++ CaM & PKC Receptors are selective to  subunit & effector with which they couple

22. Complexity of a response is governed by many ligands, receptors & effectors

23. Non activated Insulin Receptor Activated Insulin Receptor Insulin INSULIN RECEPTOR Tyrosine Kinase-Linked Receptors Enzyme-Linked Receptors 3