Entry |
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Name |
cGMP-PKG signaling pathway - Bos taurus (cow)
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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.
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Class |
Environmental Information Processing; Signal transduction
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Pathway map |

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Other DBs |
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Organism |
Bos taurus (cow) [GN: bta]
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Gene |
281750 | EDNRB; endothelin receptor type B precursor [KO:K04198] |
536654 | GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634] |
281788 | GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635] |
515159 | GNA12; guanine nucleotide-binding protein subunit alpha-12 [KO:K04346] |
505611 | GNA13; guanine nucleotide-binding protein subunit alpha-13 isoform X2 [KO:K04639] |
407151 | TRPC6; short transient receptor potential channel 6 [KO:K04969] |
286852 | PPP3CA; serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform [KO:K04348] [EC:3.1.3.16] |
533527 | PPP3CC; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform [KO:K04348] [EC:3.1.3.16] |
790867 | PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform [KO:K04348] [EC:3.1.3.16] |
407231 | MEF2A; myocyte-specific enhancer factor 2A [KO:K09260] |
512254 | MEF2C; myocyte-specific enhancer factor 2C [KO:K04454] |
511224 | NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 [KO:K04446] |
530401 | NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 isoform X1 [KO:K17332] |
541127 | NFATC3; nuclear factor of activated T-cells, cytoplasmic 3 [KO:K17333] |
788119 | NFATC4; nuclear factor of activated T-cells, cytoplasmic 4 [KO:K17334] |
281356 | NPPC; C-type natriuretic peptide precursor [KO:K12336] |
408015 | CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C isoform X1 [KO:K04850] |
408013 | CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851] |
509779 | CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F [KO:K04853] |
100337204 | CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S isoform X1 [KO:K04857] |
282573 | KCNMA1; calcium-activated potassium channel subunit alpha-1 [KO:K04936] |
524144 | KCNU1; potassium channel subfamily U member 1 [KO:K05274] |
407176 | KCNMB1; calcium-activated potassium channel subunit beta-1 [KO:K04937] |
534568 | KCNMB2; calcium-activated potassium channel subunit beta-2 [KO:K04938] |
539609 | KCNMB3; calcium-activated potassium channel subunit beta-3 [KO:K04939] |
520448 | KCNMB4; calcium-activated potassium channel subunit beta-4 [KO:K04941] |
337925 | SLC8A1; sodium/calcium exchanger 1 precursor [KO:K05849] |
540307 | SLC8A3; sodium/calcium exchanger 3 precursor [KO:K05849] |
535881 | SLC8A2; sodium/calcium exchanger 2 isoform X1 [KO:K05849] |
515161 | ATP1A2; sodium/potassium-transporting ATPase subunit alpha-2 precursor [KO:K01539] [EC:7.2.2.13] |
282598 | ATP1A3; sodium/potassium-transporting ATPase subunit alpha-3 isoform X1 [KO:K01539] [EC:7.2.2.13] |
282562 | ATP1B2; sodium/potassium-transporting ATPase subunit beta-2 [KO:K01540] |
532844 | ATP1B3; sodium/potassium-transporting ATPase subunit beta-3 [KO:K01540] |
519758 | ATP1B1; sodium/potassium-transporting ATPase subunit beta-1 [KO:K01540] |
281773 | FXYD2; sodium/potassium-transporting ATPase subunit gamma [KO:K01538] |
507792 | GTF2IRD1; general transcription factor II-I repeat domain-containing protein 1 [KO:K03121] |
287026 | PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11] |
281985 | PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:3.1.4.11] |
515669 | PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11] |
508888 | PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11] |
317697 | ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958] |
281878 | ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959] |
281879 | ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960] |
338049 | RHOA; transforming protein RhoA precursor [KO:K04513] |
538606 | PPP1R12A; protein phosphatase 1 regulatory subunit 12A [KO:K06270] |
282318 | PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16] |
516175 | PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16] |
538829 | PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16] |
617412 | CALML6; LOW QUALITY PROTEIN: calmodulin-like protein 6 [KO:K02183] |
505964 | MYL9; myosin regulatory light polypeptide 9 [KO:K12755] |
281702 | CNGB1; cyclic nucleotide-gated cation channel beta-1 isoform a [KO:K04952] |
281971 | PDE2A; cGMP-dependent 3',5'-cyclic phosphodiesterase isoform PDE2A1 [KO:K18283] [EC:3.1.4.17] |
536636 | PDE3A; LOW QUALITY PROTEIN: cGMP-inhibited 3',5'-cyclic phosphodiesterase A [KO:K19021] [EC:3.1.4.17] |
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] |
539521 | GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630] |
530001 | PIK3CG; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform [KO:K21289] [EC:2.7.1.153] |
614838 | PIK3R5; phosphoinositide 3-kinase regulatory subunit 5 isoform X3 [KO:K21290] |
515621 | PIK3R6; phosphoinositide 3-kinase regulatory subunit 6 [KO:K21290] |
282572 | KCNJ8; ATP-sensitive inward rectifier potassium channel 8 [KO:K05001] |
282119 | VDAC1; voltage-dependent anion-selective channel protein 1 [KO:K05862] |
282120 | VDAC2; voltage-dependent anion-selective channel protein 2 [KO:K15040] |
282716 | VDAC3; voltage-dependent anion-selective channel protein 3 [KO:K15041] |
414346 | PPIF; peptidyl-prolyl cis-trans isomerase F, mitochondrial precursor [KO:K09565] [EC:5.2.1.8] |
281713 | CREB1; cyclic AMP-responsive element-binding protein 1 [KO:K05870] |
509827 | ATF2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450] |
509107 | ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374] |
281715 | CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048] |
513105 | CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048] |
513010 | CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048] |
529566 | CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X5 [KO:K09048] |
785086 | CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048] |
534129 | CREB5; cyclic AMP-responsive element-binding protein 5 [KO:K09047] |
513928 | ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049] |
615013 | BAD; bcl2-associated agonist of cell death [KO:K02158] |
514902 | VASP; vasodilator-stimulated phosphoprotein [KO:K06274] |
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Compound |
C01245 | D-myo-Inositol 1,4,5-trisphosphate |
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Reference |
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Authors |
Francis SH, Busch JL, Corbin JD, Sibley D |
Title |
cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. |
Journal |
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Reference |
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Authors |
Feil R, Kemp-Harper B |
Title |
cGMP signalling: from bench to bedside. Conference on cGMP generators, effectors and therapeutic implications. |
Journal |
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Reference |
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Authors |
Takimoto E |
Title |
Cyclic GMP-dependent signaling in cardiac myocytes. |
Journal |
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Reference |
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Authors |
Hofmann F, Feil R, Kleppisch T, Schlossmann J |
Title |
Function of cGMP-dependent protein kinases as revealed by gene deletion. |
Journal |
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Reference |
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Authors |
Kuebler WM |
Title |
The Janus-faced regulation of endothelial permeability by cyclic GMP. |
Journal |
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Reference |
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Authors |
Schlossmann J, Desch M |
Title |
IRAG and novel PKG targeting in the cardiovascular system. |
Journal |
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Reference |
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Authors |
Murthy KS |
Title |
Signaling for contraction and relaxation in smooth muscle of the gut. |
Journal |
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Reference |
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Authors |
Sanders KM, Koh SD, Ro S, Ward SM |
Title |
Regulation of gastrointestinal motility--insights from smooth muscle biology. |
Journal |
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Reference |
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Authors |
Gao Y |
Title |
The multiple actions of NO. |
Journal |
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Reference |
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Authors |
Wang X, Robinson PJ |
Title |
Cyclic GMP-dependent protein kinase and cellular signaling in the nervous system. |
Journal |
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Reference |
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Authors |
Tsai EJ, Kass DA |
Title |
Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics. |
Journal |
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Reference |
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Authors |
Villanueva C, Giulivi C |
Title |
Subcellular and cellular locations of nitric oxide synthase isoforms as determinants of health and disease. |
Journal |
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Reference |
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Authors |
Schlossmann J, Hofmann F |
Title |
cGMP-dependent protein kinases in drug discovery. |
Journal |
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Reference |
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Authors |
Kass DA, Champion HC, Beavo JA |
Title |
Phosphodiesterase type 5: expanding roles in cardiovascular regulation. |
Journal |
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Reference |
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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 |
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Reference |
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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 |
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Reference |
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Authors |
McKinsey TA, Kass DA |
Title |
Small-molecule therapies for cardiac hypertrophy: moving beneath the cell surface. |
Journal |
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Reference |
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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 |
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Reference |
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Authors |
Costa AD, Pierre SV, Cohen MV, Downey JM, Garlid KD |
Title |
cGMP signalling in pre- and post-conditioning: the role of mitochondria. |
Journal |
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Reference |
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Authors |
Boengler K, Schulz R, Heusch G |
Title |
Loss of cardioprotection with ageing. |
Journal |
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Reference |
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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 |
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Reference |
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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 |
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Reference |
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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 |
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Related pathway |
bta04270 | Vascular smooth muscle contraction |
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KO pathway |
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