Download presentation
Presentation is loading. Please wait.
Published byMyrtle Rose Modified over 8 years ago
1
Second messenger systems: cAMP/cGMP Cyclic nucleotide production & regulation AGC family kinases Biological function
2
Cyclic Nucleotides Nucleotide cyclase Phosphodiesterase ATP GTP cAMP cGMP AMP GMP AC PDE GC Gs GoGiGt NO Ca2+
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) Wettschureck & Offermanns, 2005 cAMP AMP PDE3 Increased depolarization cAMP increases Ca 2+ influx Reduced action potential Reduced Ca 2+ efflux Increased Ca 2+ influx Increased force
5
Nucleotide cyclases Dimeric cyclase homology domain Regulation by accessory proteins-G , 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 PKA Regulatory subunit
9
AKAP scaffold Subcellular targeting of PKA –250+ isoforms –Membrane bound Scaffold –PKA Regulatory subunit –Acylation –Anchor (receptor,etc) –PDE Spatially specific activity Smith & al 2013 DOI 10.7554/eLife.01319
10
AKAPs and cardiac contractility Adrenergic stimulation increases cardiac output – ↑ K V,I KS –Enhanced Ca signal – ↑ DHPR – ↑ RyR – ↓ Phospho- lamban-|SERCA Kritzer, et al., 2012 AKAP Target PKA
11
Refining PKA activity by AKAP modules PKA FRET reporter (Zhang 2001) Reporter + PKA anchor Reporter + PKA anchor + PDE anchor ReporterReporter + NLS Zhang et al 2001 Dodge-Kafka et al 2005 Add forskolin AC at t=0 Add cAMP at t=0
12
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
13
PKG reduces contractility Reduced Ca2+ influx Reduced contractile function
14
Gt/Transducin Rhodopsin receptor cGMP phosphodiesterase –Reduces cGMP –Closes cGMP Na+ channels –Hyperpolarizes rod –Decreases firing –Decreases [Ca 2+ ] i Reduced calcium –GC activating protein –Restoration of cGMP
Similar presentations
© 2024 SlidePlayer.com Inc.
All rights reserved.