Entry
Name
cGMP-PKG signaling pathway - Macaca mulatta (rhesus monkey)
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
Macaca mulatta (rhesus monkey) [GN:
mcc ]
Gene
712773 AGTR1; type-1 angiotensin II receptor isoform X2 [KO:K04166 ]
697329 EDNRB; endothelin receptor type B isoform X2 [KO:K04198 ]
695106 ADRA1B; alpha-1B adrenergic receptor isoform X2 [KO:K04136 ]
705680 GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634 ]
721649 GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635 ]
100429106 GNA12; guanine nucleotide-binding protein subunit alpha-12 isoform X1 [KO:K04346 ]
718144 GNA13; guanine nucleotide-binding protein subunit alpha-13 isoform X1 [KO:K04639 ]
703611 TRPC6; short transient receptor potential channel 6 [KO:K04969 ]
706955 PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform isoform X7 [KO:K04348 ] [EC:3.1.3.16 ]
708233 PPP3CC; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform isoform X2 [KO:K04348 ] [EC:3.1.3.16 ]
709773 PPP3CA; serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform [KO:K04348 ] [EC:3.1.3.16 ]
708956 MEF2A; myocyte-specific enhancer factor 2A [KO:K09260 ]
694992 MEF2C; myocyte-specific enhancer factor 2C [KO:K04454 ]
718449 MEF2D; myocyte-specific enhancer factor 2D isoform X4 [KO:K09262 ]
698089 NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 isoform X2 [KO:K04446 ]
710601 NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 isoform X1 [KO:K17332 ]
702390 NFATC3; nuclear factor of activated T-cells, cytoplasmic 3 isoform X2 [KO:K17333 ]
714785 NFATC4; nuclear factor of activated T-cells, cytoplasmic 4 isoform X2 [KO:K17334 ]
696775 GATA4; transcription factor GATA-4 isoform X1 [KO:K09183 ]
717026 NPPC; C-type natriuretic peptide precursor [KO:K12336 ]
721721 CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C isoform X13 [KO:K04850 ]
693924 CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851 ]
715787 CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F [KO:K04853 ]
708706 CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857 ]
574103 KCNMA1; calcium-activated potassium channel subunit alpha-1 [KO:K04936 ]
697748 KCNU1; potassium channel subfamily U member 1 isoform X1 [KO:K05274 ]
700624 KCNMB1; calcium-activated potassium channel subunit beta-1 [KO:K04937 ]
710221 KCNMB2; calcium-activated potassium channel subunit beta-2 [KO:K04938 ]
709856 KCNMB3; calcium-activated potassium channel subunit beta-3 isoform X4 [KO:K04939 ]
717360 KCNMB4; calcium-activated potassium channel subunit beta-4 [KO:K04941 ]
718243 SLC8A2; sodium/calcium exchanger 2 isoform X1 [KO:K05849 ]
574193 SLC8A1; sodium/calcium exchanger 1 precursor [KO:K05849 ]
713061 SLC8A3; sodium/calcium exchanger 3 isoform X2 [KO:K05849 ]
719623 ATP1A4; sodium/potassium-transporting ATPase subunit alpha-4 isoform X1 [KO:K01539 ] [EC:7.2.2.13 ]
716093 ATP1B2; sodium/potassium-transporting ATPase subunit beta-2 [KO:K01540 ]
700443 ATP1B1; sodium/potassium-transporting ATPase subunit beta-1 [KO:K01540 ]
716682 ATP1B3; sodium/potassium-transporting ATPase subunit beta-3 [KO:K01540 ]
704049 sodium/potassium-transporting ATPase subunit gamma isoform X1 [KO:K01538 ]
701951 PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858 ] [EC:3.1.4.11 ]
718418 PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X3 [KO:K05858 ] [EC:3.1.4.11 ]
718387 PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858 ] [EC:3.1.4.11 ]
717764 PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858 ] [EC:3.1.4.11 ]
703669 ITPR1; inositol 1,4,5-trisphosphate receptor type 1 isoform X1 [KO:K04958 ]
708714 ITPR2; inositol 1,4,5-trisphosphate receptor type 2 isoform X1 [KO:K04959 ]
718040 ITPR3; inositol 1,4,5-trisphosphate receptor type 3 isoform X1 [KO:K04960 ]
707768 ATP2A3; sarcoplasmic/endoplasmic reticulum calcium ATPase 3 isoform X3 [KO:K05853 ] [EC:7.2.2.10 ]
708058 ATP2A1; sarcoplasmic/endoplasmic reticulum calcium ATPase 1 isoform X1 [KO:K05853 ] [EC:7.2.2.10 ]
710702 ATP2A2; sarcoplasmic/endoplasmic reticulum calcium ATPase 2 isoform X3 [KO:K05853 ] [EC:7.2.2.10 ]
695735 PPP1R12A; protein phosphatase 1 regulatory subunit 12A [KO:K06270 ]
703302 PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269 ] [EC:3.1.3.16 ]
709935 PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269 ] [EC:3.1.3.16 ]
721735 PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269 ] [EC:3.1.3.16 ]
703514 CALML6; calmodulin-like protein 6 isoform X1 [KO:K02183 ]
693753 CALML4; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183 ]
709784 MYL9; myosin regulatory light polypeptide 9 [KO:K12755 ]
706073 CNGB1; cyclic nucleotide-gated cation channel beta-1 [KO:K04952 ]
717256 OPRD1; delta-type opioid receptor isoform X1 [KO:K04213 ]
699310 GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630 ]
703780 GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630 ]
708940 GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 isoform X1 [KO:K04630 ]
698857 PIK3CG; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform [KO:K21289 ] [EC:2.7.1.153 ]
722027 PIK3R5; phosphoinositide 3-kinase regulatory subunit 5 isoform X1 [KO:K21290 ]
722023 PIK3R6; phosphoinositide 3-kinase regulatory subunit 6 [KO:K21290 ]
706369 KCNJ8; ATP-sensitive inward rectifier potassium channel 8 [KO:K05001 ]
710045 VDAC1; voltage-dependent anion-selective channel protein 1 [KO:K05862 ]
704257 VDAC2; voltage-dependent anion-selective channel protein 2 [KO:K15040 ]
705116 VDAC3; voltage-dependent anion-selective channel protein 3 isoform X1 [KO:K15041 ]
708717 CREB1; cyclic AMP-responsive element-binding protein 1 [KO:K05870 ]
699072 ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450 ]
703965 ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374 ]
714981 CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048 ]
713391 CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048 ]
696350 CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048 ]
721825 CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048 ]
715951 CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048 ]
697718 CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047 ]
717050 ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049 ]
717740 BAD; bcl2-associated agonist of cell death [KO:K02158 ]
716022 VASP; vasodilator-stimulated phosphoprotein isoform X1 [KO:K06274 ]
721821 MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369 ] [EC:2.7.12.2 ]
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
mcc04270 Vascular smooth muscle contraction
KO pathway
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