Entry
Name
cGMP-PKG signaling pathway - Bos taurus (cow)
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
Other DBs
Organism
Bos taurus (cow) [GN:
bta ]
Gene
100337204 CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S isoform X1 [KO:K04857 ]
281356 NPPC; C-type natriuretic peptide precursor [KO:K12336 ]
281702 CNGB1; cyclic nucleotide-gated cation channel beta-1 isoform a [KO:K04952 ]
281713 CREB1; cyclic AMP-responsive element-binding protein 1 [KO:K05870 ]
281715 CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048 ]
281750 EDNRB; endothelin receptor type B precursor [KO:K04198 ]
281773 FXYD2; sodium/potassium-transporting ATPase subunit gamma [KO:K01538 ]
281788 GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635 ]
281790 GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630 ]
281791 GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630 ]
281878 ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959 ]
281879 ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960 ]
281918 IRAG1; inositol 1,4,5-triphosphate receptor associated 1 isoform a [KO:K12337 ]
281971 PDE2A; cGMP-dependent 3',5'-cyclic phosphodiesterase isoform PDE2A1 [KO:K18283 ] [EC:3.1.4.17 ]
281985 PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858 ] [EC:3.1.4.11 ]
282119 VDAC1; voltage-dependent anion-selective channel protein 1 [KO:K05862 ]
282120 VDAC2; voltage-dependent anion-selective channel protein 2 [KO:K15040 ]
282318 PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269 ] [EC:3.1.3.16 ]
282562 ATP1B2; sodium/potassium-transporting ATPase subunit beta-2 [KO:K01540 ]
282572 KCNJ8; ATP-sensitive inward rectifier potassium channel 8 [KO:K05001 ]
282573 KCNMA1; calcium-activated potassium channel subunit alpha-1 [KO:K04936 ]
282598 ATP1A3; sodium/potassium-transporting ATPase subunit alpha-3 isoform X1 [KO:K01539 ] [EC:7.2.2.13 ]
282716 VDAC3; voltage-dependent anion-selective channel protein 3 [KO:K15041 ]
287026 PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858 ] [EC:3.1.4.11 ]
317697 ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958 ]
337925 SLC8A1; sodium/calcium exchanger 1 precursor [KO:K05849 ]
407151 TRPC6; short transient receptor potential channel 6 [KO:K04969 ]
407176 KCNMB1; calcium-activated potassium channel subunit beta-1 [KO:K04937 ]
407231 MEF2A; myocyte-specific enhancer factor 2A [KO:K09260 ]
408013 CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851 ]
408015 CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C isoform X1 [KO:K04850 ]
414346 PPIF; peptidyl-prolyl cis-trans isomerase F, mitochondrial precursor [KO:K09565 ] [EC:5.2.1.8 ]
505611 GNA13; guanine nucleotide-binding protein subunit alpha-13 [KO:K04639 ]
505964 MYL9; myosin regulatory light polypeptide 9 [KO:K12755 ]
508888 PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858 ] [EC:3.1.4.11 ]
509107 ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374 ]
509779 CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F [KO:K04853 ]
509827 ATF2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450 ]
511224 NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 [KO:K04446 ]
512254 MEF2C; myocyte-specific enhancer factor 2C [KO:K04454 ]
513010 CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048 ]
513105 CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048 ]
513928 ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049 ]
514902 VASP; vasodilator-stimulated phosphoprotein [KO:K06274 ]
515159 GNA12; guanine nucleotide-binding protein subunit alpha-12 [KO:K04346 ]
515621 PIK3R6; phosphoinositide 3-kinase regulatory subunit 6 [KO:K21290 ]
515669 PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858 ] [EC:3.1.4.11 ]
516175 PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269 ] [EC:3.1.3.16 ]
519758 ATP1B1; sodium/potassium-transporting ATPase subunit beta-1 [KO:K01540 ]
520448 KCNMB4; calcium-activated potassium channel subunit beta-4 [KO:K04941 ]
524144 KCNU1; potassium channel subfamily U member 1 [KO:K05274 ]
529566 CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X5 [KO:K09048 ]
530001 PIK3CG; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform [KO:K21289 ] [EC:2.7.1.153 ]
530401 NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 isoform X1 [KO:K17332 ]
532844 ATP1B3; sodium/potassium-transporting ATPase subunit beta-3 [KO:K01540 ]
533527 PPP3CC; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform [KO:K04348 ] [EC:3.1.3.16 ]
534129 CREB5; cyclic AMP-responsive element-binding protein 5 [KO:K09047 ]
534568 KCNMB2; calcium-activated potassium channel subunit beta-2 [KO:K04938 ]
535881 SLC8A2; sodium/calcium exchanger 2 isoform X1 [KO:K05849 ]
536636 PDE3A; LOW QUALITY PROTEIN: cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A [KO:K19021 ] [EC:3.1.4.17 ]
536654 GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634 ]
538606 PPP1R12A; protein phosphatase 1 regulatory subunit 12A [KO:K06270 ]
538829 PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269 ] [EC:3.1.3.16 ]
539521 GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630 ]
539609 KCNMB3; calcium-activated potassium channel subunit beta-3 [KO:K04939 ]
540307 SLC8A3; sodium/calcium exchanger 3 precursor [KO:K05849 ]
541127 NFATC3; nuclear factor of activated T-cells, cytoplasmic 3 [KO:K17333 ]
614838 PIK3R5; phosphoinositide 3-kinase regulatory subunit 5 isoform X3 [KO:K21290 ]
615013 BAD; bcl2-associated agonist of cell death [KO:K02158 ]
617412 CALML6; LOW QUALITY PROTEIN: calmodulin-like protein 6 [KO:K02183 ]
785086 CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048 ]
788119 NFATC4; nuclear factor of activated T-cells, cytoplasmic 4 [KO:K17334 ]
790867 PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform [KO:K04348 ] [EC:3.1.3.16 ]
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
bta04270 Vascular smooth muscle contraction
KO pathway