Entry
Name
cGMP-PKG signaling pathway - Echinops telfairi (small Madagascar hedgehog)
Description
Cyclic GMP (cGMP) is the intracellular second messenger that mediates the action of nitric oxide (NO) and natriuretic peptides (NPs), regulating a broad array of physiologic processes. The elevated intracellular cGMP level exerts its physiological action through two forms of cGMP-dependent protein kinase (PKG), cGMP-regulated phosphodiesterases (PDE2, PDE3) and cGMP-gated cation channels, among which PKGs might be the primary mediator. PKG1 isoform-specific activation of established substrates leads to reduction of cytosolic calcium concentration and/or decrease in the sensitivity of myofilaments to Ca2+ (Ca2+-desensitization), resulting in smooth muscle relaxation. In cardiac myocyte, PKG directly phosphorylates a member of the transient potential receptor canonical channel family, TRPC6, suppressing this nonselective ion channel's Ca2+ conductance, G-alpha-q agonist-induced NFAT activation, and myocyte hypertrophic responses. PKG also opens mitochondrial ATP-sensitive K+ (mitoKATP) channels and subsequent release of ROS triggers cardioprotection.
Class
Environmental Information Processing; Signal transduction
BRITE hierarchy
Pathway map
Ortholog table
Other DBs
Organism
Echinops telfairi (small Madagascar hedgehog) [GN:
etf ]
Gene
101637893 guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634 ]
101648105 GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635 ]
101637962 GNA12; guanine nucleotide-binding protein subunit alpha-12 [KO:K04346 ]
101645418 GNA13; guanine nucleotide-binding protein subunit alpha-13 [KO:K04639 ]
101639952 PPP3CA; serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform [KO:K04348 ] [EC:3.1.3.16 ]
101642124 PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform isoform X4 [KO:K04348 ] [EC:3.1.3.16 ]
101638696 PPP3CC; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform isoform X1 [KO:K04348 ] [EC:3.1.3.16 ]
101642066 MEF2A; myocyte-specific enhancer factor 2A isoform X3 [KO:K09260 ]
101659295 MEF2C; myocyte-specific enhancer factor 2C isoform X1 [KO:K04454 ]
101649668 MEF2D; myocyte-specific enhancer factor 2D isoform X1 [KO:K09262 ]
101641174 NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 isoform X1 [KO:K04446 ]
101639478 NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 [KO:K17332 ]
101664022 NFATC3; nuclear factor of activated T-cells, cytoplasmic 3 [KO:K17333 ]
101645262 NFATC4; nuclear factor of activated T-cells, cytoplasmic 4 isoform X1 [KO:K17334 ]
101656925 CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C [KO:K04850 ]
101651425 CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851 ]
101662493 CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F [KO:K04853 ]
101658956 CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857 ]
101650522 KCNMA1; LOW QUALITY PROTEIN: calcium-activated potassium channel subunit alpha-1 [KO:K04936 ]
101658085 KCNMB1; calcium-activated potassium channel subunit beta-1 [KO:K04937 ]
101641224 KCNMB2; calcium-activated potassium channel subunit beta-2 [KO:K04938 ]
101642167 KCNMB3; calcium-activated potassium channel subunit beta-3 [KO:K04939 ]
101654573 KCNMB4; calcium-activated potassium channel subunit beta-4 [KO:K04941 ]
101650239 ATP1B1; sodium/potassium-transporting ATPase subunit beta-1 [KO:K01540 ]
101656219 ATP1B2; sodium/potassium-transporting ATPase subunit beta-2 [KO:K01540 ]
101663646 ATP1B3; sodium/potassium-transporting ATPase subunit beta-3 [KO:K01540 ]
123520896 FXYD2; sodium/potassium-transporting ATPase subunit gamma isoform X1 [KO:K01538 ]
101663006 LOW QUALITY PROTEIN: regulator of G-protein signaling 2 [KO:K18154 ]
101651304 PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858 ] [EC:3.1.4.11 ]
101656854 PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X3 [KO:K05858 ] [EC:3.1.4.11 ]
101648395 IRAG1; inositol 1,4,5-triphosphate receptor associated 1 isoform X1 [KO:K12337 ]
101646224 PPP1R12A; protein phosphatase 1 regulatory subunit 12A isoform X5 [KO:K06270 ]
101663948 PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform X1 [KO:K06269 ] [EC:3.1.3.16 ]
101656573 LOW QUALITY PROTEIN: serine/threonine-protein phosphatase PP1-gamma catalytic subunit-like [KO:K06269 ] [EC:3.1.3.16 ]
101658651 GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630 ]
101643144 GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630 ]
101641371 GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 isoform X1 [KO:K04630 ]
101649703 PIK3CG; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform [KO:K21289 ] [EC:2.7.1.153 ]
101641665 PIK3R6; phosphoinositide 3-kinase regulatory subunit 6 [KO:K21290 ]
101638717 PIK3R5; phosphoinositide 3-kinase regulatory subunit 5 [KO:K21290 ]
101650694 KCNJ8; ATP-sensitive inward rectifier potassium channel 8 [KO:K05001 ]
101656727 VDAC1; voltage-dependent anion-selective channel protein 1 [KO:K05862 ]
101653907 voltage-dependent anion-selective channel protein 1-like [KO:K05862 ]
101649902 VDAC2; voltage-dependent anion-selective channel protein 2 [KO:K15040 ]
101642569 VDAC3; voltage-dependent anion-selective channel protein 3 isoform X2 [KO:K15041 ]
101642037 LOW QUALITY PROTEIN: peptidyl-prolyl cis-trans isomerase F, mitochondrial-like [KO:K09565 ] [EC:5.2.1.8 ]
101646557 CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870 ]
101656771 ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450 ]
101650311 ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374 ]
101653565 CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048 ]
101648900 CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048 ]
101654666 CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X2 [KO:K09048 ]
101654039 CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X3 [KO:K09048 ]
101639977 CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048 ]
101648034 CREB5; cyclic AMP-responsive element-binding protein 5 isoform X2 [KO:K09047 ]
101662802 ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X2 [KO:K09049 ]
Compound
C01245 D-myo-Inositol 1,4,5-trisphosphate
Reference
Authors
Francis SH, Busch JL, Corbin JD, Sibley D
Title
cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action.
Journal
Reference
Authors
Feil R, Kemp-Harper B
Title
cGMP signalling: from bench to bedside. Conference on cGMP generators, effectors and therapeutic implications.
Journal
Reference
Authors
Takimoto E
Title
Cyclic GMP-dependent signaling in cardiac myocytes.
Journal
Reference
Authors
Hofmann F, Feil R, Kleppisch T, Schlossmann J
Title
Function of cGMP-dependent protein kinases as revealed by gene deletion.
Journal
Reference
Authors
Kuebler WM
Title
The Janus-faced regulation of endothelial permeability by cyclic GMP.
Journal
Reference
Authors
Schlossmann J, Desch M
Title
IRAG and novel PKG targeting in the cardiovascular system.
Journal
Reference
Authors
Murthy KS
Title
Signaling for contraction and relaxation in smooth muscle of the gut.
Journal
Reference
Authors
Sanders KM, Koh SD, Ro S, Ward SM
Title
Regulation of gastrointestinal motility--insights from smooth muscle biology.
Journal
Reference
Authors
Gao Y
Title
The multiple actions of NO.
Journal
Reference
Authors
Wang X, Robinson PJ
Title
Cyclic GMP-dependent protein kinase and cellular signaling in the nervous system.
Journal
Reference
Authors
Tsai EJ, Kass DA
Title
Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics.
Journal
Reference
Authors
Villanueva C, Giulivi C
Title
Subcellular and cellular locations of nitric oxide synthase isoforms as determinants of health and disease.
Journal
Reference
Authors
Schlossmann J, Hofmann F
Title
cGMP-dependent protein kinases in drug discovery.
Journal
Reference
Authors
Kass DA, Champion HC, Beavo JA
Title
Phosphodiesterase type 5: expanding roles in cardiovascular regulation.
Journal
Reference
Authors
Uckert S, Hedlund P, Andersson KE, Truss MC, Jonas U, Stief CG
Title
Update on phosphodiesterase (PDE) isoenzymes as pharmacologic targets in urology: present and future.
Journal
Reference
Authors
Yan C, Kim D, Aizawa T, Berk BC
Title
Functional interplay between angiotensin II and nitric oxide: cyclic GMP as a key mediator.
Journal
Reference
Authors
McKinsey TA, Kass DA
Title
Small-molecule therapies for cardiac hypertrophy: moving beneath the cell surface.
Journal
Reference
Authors
Koitabashi N, Aiba T, Hesketh GG, Rowell J, Zhang M, Takimoto E, Tomaselli GF, Kass DA
Title
Cyclic GMP/PKG-dependent inhibition of TRPC6 channel activity and expression negatively regulates cardiomyocyte NFAT activation Novel mechanism of cardiac stress modulation by PDE5 inhibition.
Journal
Reference
Authors
Costa AD, Pierre SV, Cohen MV, Downey JM, Garlid KD
Title
cGMP signalling in pre- and post-conditioning: the role of mitochondria.
Journal
Reference
Authors
Boengler K, Schulz R, Heusch G
Title
Loss of cardioprotection with ageing.
Journal
Reference
Authors
Gao Y, Portugal AD, Liu J, Negash S, Zhou W, Tian J, Xiang R, Longo LD, Raj JU
Title
Preservation of cGMP-induced relaxation of pulmonary veins of fetal lambs exposed to chronic high altitude hypoxia: role of PKG and Rho kinase.
Journal
Reference
Authors
Li Z, Xi X, Du X
Title
A mitogen-activated protein kinase-dependent signaling pathway in the activation of platelet integrin alpha IIbbeta3.
Journal
Reference
Authors
Xie J, Cha SK, An SW, Kuro-O M, Birnbaumer L, Huang CL
Title
Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart.
Journal
Related pathway
etf04270 Vascular smooth muscle contraction
KO pathway
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