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MF_7_11 - G Protein Signaling Protein Hormone Receptor(7 TM...

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Unformatted text preview: G Protein Signaling Protein Hormone Receptor (7 TM, Serpentine, GPCR) Heterotrimeric G Protein ( α, β, γ ) Heterotrimeric GDP released from alpha, and GTP binds α and β γ disassociate disassociate Target Activated by α or β γ Target Second Messenger Second Target Second G Protein Receptors G Protein Coupled Receptors Protein β -adrenergic receptor -adrenergic adrenalin Gs α -adrenergic -adrenergic adrenalin Gi Rhodopsin vision Gt Smell Receptors 1000 in human genome Acetylcholine Receptor muscarinic Types of G Proteins G Proteins Have Diverse Functions; Proteins G Proteins Famiies are Named for the α Subunits Proteins Activation Cartoon Generic G Protein Signaling: Activation Generic G protein with GTP α separates from β γ Targets activated Later, to turn off, Gα-GTP hydrolyzes Its own GTP to GDP Rebind β γ and return to resting state Signaling With Molecular Switches Signaling 5Heterotrimeric G proteins: proteins: 5Guanine Nucleotide Guanine Exchance Factor Exchance 5Stimulates GDP release 57 TM Receptor is GEF TM GEF 5RGS is GAP RGS GAP 5Regulator of G Regulator Protein Signaling Protein 5GTPase activating protein Structure G Protein Structure Protein Switch Regions 3 D View of the G Protein Structure View 1GOT Heterotrimeric G Protein with GDP Note: beta subunit is a barrel of beta sheet structures alpha has nucleotide binding domain gamma bound to beta through coiled coil alpha contacts beta/gamma through switch regions GDP or GTP state of alpha will change switch regions, and mediate release of beta/gamma G Protein Switch Regions: Conformational Change Induced by GTP Binding. Lodish 5th Fig. 13-8. 13-8. Receptor & G Protein 7TM Receptor and G Protein Interaction Interaction Adrenaline Pathway Adrenalin Pathway Adrenalin Stimulation of the Stimulation causes: causes: β -adrenergic receptor Increase of heart rate Increase in breakdown of glycogen in muscle Inhibition of glycogen synthesis in muscle Breakdown of tri-glyceride in fat cell Signal: adrenalin Receptor: β -adrenergic Receptor Receptor: -adrenergic G protein: Gs ( αs, β , γ ) protein: Enzyme: Adenylyl Cyclase 2° Messenger: cAMP Target : Protein Kinase A PKA cAMP dependent kinase AC/PKA Adenylyl Cyclase and Protein Kinase A Adenylyl Gene Expression PKA Pathway Regulates Metabolism and Gene Expression: PKA Note: Connect with Dr. Mensa-Wilmot materials on transcription Adaptation Turning off the β -adrenergic Signaling -adrenergic Adrenalin released from receptor Gs-alpha hydrolyzes GTP Gs-alpha RGS is the Regulator of GTPase Signaling RGS is a GTPase Activating Protein: GAP RGS stimulates GTPase by Gs Phosphodiesterase cleaves cAMP PKA turns off as regulatory and catalytic subunits assemble Phosphoprotein Phosphatase turns off PKA targets Kinase phosphorylates receptor in active state G protein coupled receptor kinases (GRKs) β -adrenergic receptor kinase -adrenergic β -arrestin binds to phosphorylated receptor to stop signal -arrestin BARK β -adrenergic receptor kinase (BARK) -adrenergic New findings also implicate β -arrestin in other functions: Promote endocytosis Activation of MAP kinase (RTK) by cross-talk Scaffold protein to organize signaling pathways Lefkowitz and Shenoy. Science 308, 512-517 (2005) Retina G protein Signaling in the Retina protein Signal: light Receptor: rhodopsin (opsin plus 11-cis retinal) G protein: Transducin. Gt ( α τ , β , γ ) protein: β, Enzyme: cGMP phosphodiesterase 2° Messenger: decrease in cGMP cGMP is ligand for ligand gated Na+ channel Cyclic Nucleotide Gated Channel: Cousin of K+ channel Target : close the sodium channel Cell repolarizes Cell No release of inhibitory transmitter Post-synaptic cell fires and sends signal to brain Photoreceptor Cell G protein Signaling Signaling in the Retina Dark and Light Light Closes Cation Channels in the Retina cGMP Gated Channel G Protein Signaling in the Retina leads Protein to Closing of Ligand Gated Na+ Channels Channels Rhodopsin Kinase/Arrestin Rhodopsin Kinase and Arrestin Similar to Similar β -ARK and β -arrestin in -arrestin the adrenalin pathway pathway Amplification Signal Amplification in G Protein Signaling in in the Retina and in the Adrenergic System Summary Summary of G Protein Signaling Summary cell stimulus receptor target result annel annel fat cell (adipocyte) epinephrine receptor adenyl cyclase active protein kinase A rod cell of retina rhodopsin transducin cGMP PDE decrease in cGMP close sodium close epinephrine (adrenalin) photon of light transducer Gs protein messenger increase in cAMP ...
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