Entry
Name
cGMP-PKG signaling pathway - Ursus americanus (American black bear)
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
Ursus americanus (American black bear) [GN:
uar ]
Gene
123801077 EDNRB; LOW QUALITY PROTEIN: endothelin receptor type B [KO:K04198 ]
123800552 ADRA1D; LOW QUALITY PROTEIN: alpha-1D adrenergic receptor [KO:K04137 ]
123781527 GNAQ; guanine nucleotide-binding protein G(q) subunit alpha isoform X1 [KO:K04634 ]
123793965 GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635 ]
123802492 GNA12; guanine nucleotide-binding protein subunit alpha-12 [KO:K04346 ]
123802930 GNA13; guanine nucleotide-binding protein subunit alpha-13 [KO:K04639 ]
123792490 TRPC6; short transient receptor potential channel 6 isoform X1 [KO:K04969 ]
123788880 PPP3CA; serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform isoform X1 [KO:K04348 ] [EC:3.1.3.16 ]
123782828 PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform isoform X1 [KO:K04348 ] [EC:3.1.3.16 ]
123777460 PPP3CC; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform isoform X1 [KO:K04348 ] [EC:3.1.3.16 ]
123790791 MEF2A; myocyte-specific enhancer factor 2A isoform X1 [KO:K09260 ]
123791493 MEF2C; myocyte-specific enhancer factor 2C isoform X1 [KO:K04454 ]
123783420 MEF2D; myocyte-specific enhancer factor 2D isoform X1 [KO:K09262 ]
123787495 NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 isoform X1 [KO:K04446 ]
123799385 NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 isoform X1 [KO:K17332 ]
123803502 NFATC3; nuclear factor of activated T-cells, cytoplasmic 3 isoform X1 [KO:K17333 ]
123795735 NFATC4; nuclear factor of activated T-cells, cytoplasmic 4 isoform X1 [KO:K17334 ]
123777895 CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C [KO:K04850 ]
123798762 CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851 ]
123797184 CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853 ]
123785763 CACNA1S; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857 ]
123782863 KCNMA1; calcium-activated potassium channel subunit alpha-1 isoform X1 [KO:K04936 ]
123788586 KCNMB1; calcium-activated potassium channel subunit beta-1 [KO:K04937 ]
123786405 KCNMB2; calcium-activated potassium channel subunit beta-2 [KO:K04938 ]
123786408 KCNMB3; calcium-activated potassium channel subunit beta-3 [KO:K04939 ]
123787130 KCNMB4; calcium-activated potassium channel subunit beta-4 [KO:K04941 ]
123792133 ATP1B2; sodium/potassium-transporting ATPase subunit beta-2 isoform X1 [KO:K01540 ]
123792376 ATP1B1; sodium/potassium-transporting ATPase subunit beta-1 [KO:K01540 ]
123788438 ATP1B3; sodium/potassium-transporting ATPase subunit beta-3 [KO:K01540 ]
123792608 sodium/potassium-transporting ATPase subunit gamma-like isoform X1 [KO:K01538 ]
123799710 PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858 ] [EC:3.1.4.11 ]
123804253 PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858 ] [EC:3.1.4.11 ]
123799165 ITPR1; inositol 1,4,5-trisphosphate receptor type 1 isoform X1 [KO:K04958 ]
123786570 IRAG1; inositol 1,4,5-triphosphate receptor associated 1 isoform X1 [KO:K12337 ]
123780848 PPP1R12A; protein phosphatase 1 regulatory subunit 12A isoform X1 [KO:K06270 ]
123795104 GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630 ]
123789354 GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630 ]
123798684 GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630 ]
123780203 IRS4; LOW QUALITY PROTEIN: insulin receptor substrate 4 [KO:K17446 ]
123789397 PIK3CG; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform [KO:K21289 ] [EC:2.7.1.153 ]
123792094 PIK3R6; phosphoinositide 3-kinase regulatory subunit 6 isoform X1 [KO:K21290 ]
123792093 PIK3R5; phosphoinositide 3-kinase regulatory subunit 5 isoform X1 [KO:K21290 ]
123801688 KCNJ8; ATP-sensitive inward rectifier potassium channel 8 [KO:K05001 ]
123790351 VDAC1; voltage-dependent anion-selective channel protein 1 [KO:K05862 ]
123782868 VDAC2; voltage-dependent anion-selective channel protein 2 [KO:K15040 ]
123780315 VDAC3; voltage-dependent anion-selective channel protein 3 isoform X1 [KO:K15041 ]
123798247 CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870 ]
123794100 ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450 ]
123780649 ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374 ]
123799579 CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048 ]
123781164 CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048 ]
123788905 CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048 ]
123796787 CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048 ]
123783374 CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048 ]
123789128 CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047 ]
123790975 ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [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
uar04270 Vascular smooth muscle contraction
KO pathway
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