Membrane associated receptor transfers the information. Second messengers relay information

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1 Membrane associated receptor transfers the information Most signals are polar and large Few of the signals are nonpolar Receptors are intrinsic membrane proteins Extracellular and intracellular domains Interaction of the signal with the extracellular domain => structural changes with transmission to intracellular domain Second messengers relay information Ability to diffuse to other cellular compartments Amplification of the signal Enzyme activation Membrane channels Some second messengers are common in multiple signaling pathways Permits fine tuning but can pose problems 1

2 Protein phosphorylation is a common means of information transfer Many second messengers elicit responses by activating protein kinases Phosphorylation of proteins results in conformation changes Last longer than changes in concentrations of second messengers Reversible Termination of the signal. Keeps cells responsive to new signals Failure of termination may cause problems (uncontrolled cell growth. Degradation of the second messenger Dephosphorylation by hydrolysis 2

3 Seven-Transmembrane Helix Receptors 7TM Biological Functions Mediated by 7TM Vision (rhodopsin) Smell, Taste, Neurotransmission Hormone Secretion Chemotaxis Exocytosis Cell Growth, Development Viral Infection 3

4 3b 4

5 camp and G Proteins GTP is essential for responding to Hormones Hormone Binding stimulates GTP hydrolysis Discovery of G Protein Activated Receptor Adenylate Cyclase camp Biochemical Response Ligand + Receptor Activated Receptor Activated G Protein Activated Adenylate Cyclase Increased [camp] Activated Effector 5

6 G Protein cycles between two forms Inactive State Active State Bound to GDP Bound to GTP Heterotrimer αβγ Dissociated α + βγ dimer α subunit has GTPase Activity 6

7 7

8 G Proteins (cont.) α and γ Subunits have covalently attached fatty acid α and βγ can interact with other proteins Many G Protein molecules can be activated by one signal-bound receptor. All 7TM receptors appear to be coupled to G proteins GPCRs Many different G protein exist. G s G olf G Proteins transduce many activities Transducin G i G o Gq Adenylate Cyclase Adenylate Cyclase cgmp Phosphodiesterase Adenylate Cyclase Ca 2+ Channels Phospholipase C 8

9 Adenylate Cyclase Membrane protein 12 helices Two large intracellular domains Fig 8 Synthesis and degradation of camp Adenine Adenylate cyclase Adenine Phosphodiesterase Adenine 9

10 camp can affect a wide range of cellular processes degradation of storage fuels secretion of acid by gastric mucosa Dispersion of melanin pigment granules aggregation of blood plateletes. Opening of chloride channels Most effects of camp are mediated by activation of a single enzyme protein kinase 10

11 camp can affect gene expression Phosphorylation of a transcriptional factor camp Response Element Binding Protein (CREB) Phosphorylated CREB moves to nucleus and binds to a DNA region called CRE Switching off the signal initiated by hormone binding to 7TM Dissociation of the hormone Phosphorylation of the hormone boundreceptor followed by binding to arrestin GTPase activity of Gα subunit Hydrolysis of camp 11

12 1. Dissociation of the hormone 2. Receptor Phosphorylation and binding to arrestin GTPase activity of G α subunit 12

13 The Phosphoinositide Cascade Used by many hormones Binding of a hormone to 7TM receptor Activation of G Protein Activation of Phospholipase C Two messengers are produced Inositol 1,4,5-trisphosphate (Soluble) Diacyclglycerol (Stays in the membrane) Phospholipase C 13

14 The domain structures of three isoforms of phospholipase C Binds a lipid head group Binds phospolipid head group Binding of a G protein brings the enzyme into a catalytically active form membrane G protein 14

15 Effects of Second Messengers Inositol trisphosphate Diacylglycerol Opens Calcium Channels Binding to IP 3 -gated Channel Cooperative binding Activates Protein Kinase C Ca 2+ is required Phosphorylation of many target proteins 15

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