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Second messenger systems: cAMP/cGMP

Second messenger systems: cAMP/cGMP. Cyclic nucleotide production & regulation AGC family kinases Biological function. Cyclic Nucleotides. Nucleotide cyclase Phosphodiesterase. Go. Gi. Ca2+. Gt. Gs. PDE. AC. ATP GTP. AMP GMP. cAMP cGMP. GC. NO. Cyclic nucleotide pathways.

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Second messenger systems: cAMP/cGMP

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  1. Second messenger systems: cAMP/cGMP • Cyclic nucleotide production & regulation • AGC family kinases • Biological function

  2. Cyclic Nucleotides • Nucleotide cyclase • Phosphodiesterase Go Gi Ca2+ Gt Gs PDE AC ATP GTP AMP GMP cAMP cGMP GC NO

  3. Cyclic nucleotide pathways • LigandReceptorGs/GoACcAMP • LigandReceptorGi--|ACcAMP • LigandGC ReceptorcGMP • NOG-cyclasecGMP • Rhodopsin receptorGtPDE--|cGMP • CaCaMPDE--|cAMP

  4. Competitive control of AC (heart) Sympathetic NS (fight of flight) Parasympathetic NS (rest or relax) Reduced action potential Increased depolarization cAMP increases Ca2+ influx Increased force Reduced Ca2+ efflux Increased Ca2+ influx cAMP AMP PDE3 Wettschureck & Offermanns, 2005

  5. Nucleotide cyclases • Dimeric cyclase homology domain • Regulation by accessory proteins-Ga, CaM,… Sunahara & Taussig., 2002

  6. Cyclic Nucleotide Effectors • Cyclic nucleotide kinases (ser/thr) • PKA • PKG • cGMP binding displaces autoinhibitory domain • BKCa, IP3R, CFTR • cGMP ion channel • cAMP sodium channel

  7. AGC Kinases • Allosteric regulation • Cyclic nucleotides, PIP3, DAG • PKA • cAMP causes release of regulatory subunit • PKG • cGMP binding exposes active site • PKC • DAG (& calcium) cause membrane association • PDK • PIP3 causes membrane association

  8. PKA • Ubiquitous, multifunctional • Two of 3 catalytic subunits • Two of 2 regulatory subunits • cAMP binding displaces regulatory subunit • Transcription factors • CREB, TTF-1, GATA-4 • Metabolic processes • Glycogen phosphorylase kinase (GPK), GS • Ion channels • AMPA, CFTR

  9. AKAP scaffold • Subcellular targeting of PKA • 250+ isoforms • Membrane bound • Scaffold • PKA Regulatory subunit • Acylation • Anchor (receptor,etc) • PDE • Spatially specific activity PKA Regulatory subunit PKA regulatory AKAP

  10. AKAPs a cardiac contractility • Adrenergic stimulation increases cardiac output • ↑ KV ,IKS • EnhancedCa signal • ↑DHPR • ↑ RyR • ↓Phospho-lamban-|SERCA Mauban, et al., 2009

  11. PKG/ G Kinase • cGMP production • Guanylate cyclase receptor • Nitric oxide • PKG • Ser/Thr • Type I: soluble, neural & smooth muscle • Type II: membrane bound, gut • Inhibits cell proliferation • MAPK stimulates differentiation • VASP actin binding protein

  12. PKG reduces contractility • Reduced Ca2+ influx • Reduced contractile function

  13. Gt/Transducin • Rhodopsin receptor • cGMP phosphodiesterase • Reduces cGMP • Closes cGMP Na+ channels • Hyperpolarizes rod • Decreases firing • Decreases [Ca2+]i • Reduced calcium • GC activating protein • Restoration of cGMP

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