Biosignals, Chapter 8, rearranged, Part I

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1 Biosignals, Chapter 8, rearranged, Part I

2 Nicotinic Acetylcholine Receptor: A Ligand-Binding Ion Channel

3 Classes of Receptor Proteins in Eukaryotes,

4 Heterotrimeric G Proteins Signaling View the Heterotrimeric G Proteins animation

5 Step-by-Step GPCR Activation 1. Ligand-induced conformational changes in the GPCR 2. Receptor-mediated stimulation of guanine nucleotide exchange GTP replaces GDP. 3. Regulation of downstream effector processes by G α GTP and G βγ complexes 4. Termination of signal

6 GPCR Activation Synopsis

7 Step-by-Step GPCR Activation 1. Ligand-induced conformational changes in the GPCR 2. Receptor-mediated stimulation of guanine nucleotide exchange GTP replaces GDP. 3. Regulation of downstream effector processes by G α GTP and G βγ complexes 4. Termination of signal

8 The β2-adrenergic Receptor, A GPCR Epinephrine (ligand), a catecholamine, binds to the receptor and leads to a conformational change.

9 PKA s Role in Epinephrine (β2 Bound) and Glucagon

10 Signal Amplification

11 GPCRs and Controlled by GEFs and GAPs (The G Protein Cycle) GEF Guanine nucleotide exchange factor Promote GDP-GTP exchange Activate signaling GAP GTPase activating proteins Stimulate intrinsic GTP hydrolysis activity Inhibit signal transduction

12 Termination of GPCR-Mediated Signaling Receptor is desensitized after G αβγ dissociation. G protein coupled receptor kinases (GRK) phosphorylate the GPCR cytoplasmic domain on Ser and Thr residues.

13 β-adrenergic Receptor Kinase (βark), a GRK Recruited to the membrane by G βγ Phosphorylation provides a docking site for β-arrestin, which prevents reformation of the G αβγ complex.

14 GPCR Signal Transduction Systems Abbreviation Protein name Function A C Adenylate cyclase Enzyme that produces c A M P Beta A R Beta-Adrenergic receptor Membrane-spanning receptor that binds epinephrine Beta A R K Beta-Adrenergic receptor kinase Specific G protein-coupled receptor kinase enzyme that acts on betaadrenergic receptors C A M K Positive 2 upper C-a ion / Enzyme that phosphorylates and inhibits glycogen synthase calmondulin kinase G alpha G alpha protein G protein that subunit with G T P-ase activity G alpha beta Heterotrimeric G protein Complex of G alpha, G beta, and G gamma subunits associated with G P C Rs gamma G A P GTPase activating protein Protein that stimulates G T P-ase activity of G proteins to inhibit signaling G E F Guanine nucleotide Protein that promotes G D P to G T P exchange to activate signaling G P C R G protein-coupled receptor Membrane-spanning receptor associated with intracellular G proteins G R K G protein-coupled receptor kinase Enzyme that phosphorylates G P C R s P D E Phosphodiesterase Enzyme that breaks down c A M P or c G M P P H Pleckstrin homology domain Adaptor domain that binds membrane lipids P K A Protein kinase A c A M P-dependent enzyme with kinase activity P K C Protein kinase C Lipid-activated enzyme with kinase activity P L C Phospholipase C Enzyme that produces diacylglycerol and inositol triphosphate R G S Regulator of G protein signaling G T P-ase activating protein that is associated with G P C Rs

15 Other G proteins

16 8.2 G Protein-Coupled Receptor Signaling Most of the G protein-coupled receptors (GPCR) are involved in sensory perceptions such as: Vision Taste Smell Contain seven transmembrane alpha helices Also called serpentine receptors Many are glycoproteins that contain carbohydrate functional groups directly attached to the extracellular domain.

17 Sensory Perception Mechanisms and GPCR

18 GPCR-Mediated Signaling in Metabolism Different GPCR-mediated signals can be integrated within a single cell type in response to multiple extracellular stimuli. Ligand Receptor Enzyme Second messenger Glucagon Epinephrine Epinephrine glucagon receptor β2-adrenergic receptor α1-adrenergic receptor Adenylate cyclase camp G sα Adenylate cyclase camp G sα PhospholipaseC DAG, IP 3 G qα Signaling

19 Epinephrine signal when bound to α1 adrenergic receptor

20 Phosphoinositide Cascade, Part 1

21 Phosphoinositide Cascade, Part 2

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