Entry Name cGMP-PKG signaling pathway
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 transductionBRITE hierarchy
Pathway map Other DBs Orthology K01538 FXYD2, ATP1G1; sodium/potassium-transporting ATPase subunit gamma (FXYD domain-containing ion transport regulator 2)
K01539 ATP1A; sodium/potassium-transporting ATPase subunit alpha [EC:7.2.2.13 ]
K01540 ATP1B, CD298; sodium/potassium-transporting ATPase subunit beta
K02158 BAD; Bcl-2-antagonist of cell death
K03121 TFII-I, GTF2I; transcription initiation factor TFII-I
K03916 BDKRB2; bradykinin receptor B2
K04135 ADRA1A; adrenergic receptor alpha-1A
K04136 ADRA1B; adrenergic receptor alpha-1B
K04137 ADRA1D; adrenergic receptor alpha-1D
K04138 ADRA2A; adrenergic receptor alpha-2A
K04139 ADRA2B; adrenergic receptor alpha-2B
K04140 ADRA2C; adrenergic receptor alpha-2C
K04141 ADRB1; adrenergic receptor beta-1
K04142 ADRB2; adrenergic receptor beta-2
K04143 ADRB3; adrenergic receptor beta-3
K04166 AGTR1; angiotensin II receptor type 1
K04197 EDNRA; endothelin receptor type A
K04198 EDNRB; endothelin receptor type B
K04213 OPRD1; delta-type opioid receptor
K04265 ADORA1; adenosine receptor A1
K04268 ADORA3; adenosine receptor A3
K04346 GNA12; guanine nucleotide-binding protein subunit alpha-12
K04348 PPP3C, CNA; serine/threonine-protein phosphatase 2B catalytic subunit [EC:3.1.3.16 ]
K04366 RAF1; RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1 ]
K04368 MAP2K1, MEK1; mitogen-activated protein kinase kinase 1 [EC:2.7.12.2 ]
K04369 MAP2K2, MEK2; mitogen-activated protein kinase kinase 2 [EC:2.7.12.2 ]
K04374 ATF4, CREB2; cyclic AMP-dependent transcription factor ATF-4
K04378 SRF; serum response factor
K04446 NFATC1, NFAT2, NFATC; nuclear factor of activated T-cells, cytoplasmic 1
K04450 ATF2, CREBP1; cyclic AMP-dependent transcription factor ATF-2
K04454 MEF2C; MADS-box transcription enhancer factor 2C
K04513 RHOA; Ras homolog gene family, member A
K04630 GNAI; guanine nucleotide-binding protein G(i) subunit alpha
K04634 GNAQ; guanine nucleotide-binding protein G(q) subunit alpha
K04635 GNA11; guanine nucleotide-binding protein subunit alpha-11
K04639 GNA13; guanine nucleotide-binding protein subunit alpha-13
K04850 CACNA1C, CAV1.2; voltage-dependent calcium channel L type alpha-1C
K04851 CACNA1D, CAV1.3; voltage-dependent calcium channel L type alpha-1D
K04853 CACNA1F, CAV1.4; voltage-dependent calcium channel L type alpha-1F
K04857 CACNA1S, CAV1.1; voltage-dependent calcium channel L type alpha-1S
K04936 KCNMA1, KCA1.1; potassium large conductance calcium-activated channel subfamily M alpha member 1
K04937 KCNMB1; potassium large conductance calcium-activated channel subfamily M beta member 1
K04938 KCNMB2; potassium large conductance calcium-activated channel subfamily M beta member 2
K04939 KCNMB3; potassium large conductance calcium-activated channel subfamily M beta member 3
K04941 KCNMB4; potassium large conductance calcium-activated channel subfamily M beta member 4
K04948 CNGA1; cyclic nucleotide gated channel alpha 1
K04952 CNGB1; cyclic nucleotide gated channel beta 1
K04958 ITPR1; inositol 1,4,5-triphosphate receptor type 1
K04959 ITPR2; inositol 1,4,5-triphosphate receptor type 2
K04960 ITPR3; inositol 1,4,5-triphosphate receptor type 3
K04969 TRPC6; transient receptor potential cation channel subfamily C member 6
K05001 KCNJ8, KIR6.1; potassium inwardly-rectifying channel subfamily J member 8
K05274 KCNMA3, KCNU1, KCA5.1; potassium large conductance calcium-activated channel subfamily M alpha member 3
K05849 SLC8A, NCX; solute carrier family 8 (sodium/calcium exchanger)
K05862 VDAC1; voltage-dependent anion channel protein 1
K05863 SLC25A4S, ANT; solute carrier family 25 (mitochondrial adenine nucleotide translocator), member 4/5/6/31
K05870 CREB1; cyclic AMP-responsive element-binding protein 1
K06268 PPP3R, CNB; serine/threonine-protein phosphatase 2B regulatory subunit
K06269 PPP1C; serine/threonine-protein phosphatase PP1 catalytic subunit [EC:3.1.3.16 ]
K06270 PPP1R12A, MYPT1; protein phosphatase 1 regulatory subunit 12A
K06274 VASP; vasodilator-stimulated phosphoprotein
K07187 IRS2; insulin receptor substrate 2
K09047 CREB5, CREBPA; cyclic AMP-responsive element-binding protein 5
K09048 CREB3; cyclic AMP-responsive element-binding protein 3
K09049 ATF6B, CREBL1; cyclic AMP-dependent transcription factor ATF-6 beta
K09183 GATA4; GATA-binding protein 4
K09260 MEF2A; MADS-box transcription enhancer factor 2A
K09261 MEF2B; MADS-box transcription enhancer factor 2B
K09262 MEF2D; MADS-box transcription enhancer factor 2D
K09565 PPIF; peptidyl-prolyl isomerase F (cyclophilin D) [EC:5.2.1.8 ]
K12318 GUCY1A; guanylate cyclase soluble subunit alpha [EC:4.6.1.2 ]
K12319 GUCY1B; guanylate cyclase soluble subunit beta [EC:4.6.1.2 ]
K12323 ANPRA, NPR1; atrial natriuretic peptide receptor A [EC:4.6.1.2 ]
K12324 ANPRB, NPR2; atrial natriuretic peptide receptor B [EC:4.6.1.2 ]
K12334 NPPA; natriuretic peptide A
K12335 NPPB; natriuretic peptide B
K12336 NPPC; natriuretic peptide C
K12337 MRVI1, IRAG; inositol 1,4,5-triphosphate receptor-associated cGMP kinase substrate
K12755 MYL9; myosin regulatory light chain 9
K13296 PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [EC:3.1.4.17 ]
K13762 PDE5; cGMP-specific 3',5'-cyclic phosphodiesterase [EC:3.1.4.35 ]
K15040 VDAC2; voltage-dependent anion channel protein 2
K15041 VDAC3; voltage-dependent anion channel protein 3
K16172 IRS1; insulin receptor substrate 1
K17332 NFATC2, NFAT1, NFATP; nuclear factor of activated T-cells, cytoplasmic 2
K17333 NFATC3, NFAT4; nuclear factor of activated T-cells, cytoplasmic 3
K17334 NFATC4, NFAT3; nuclear factor of activated T-cells, cytoplasmic 4
K17445 IRS3; insulin receptor substrate 3
K17446 IRS4; insulin receptor substrate 4
K17751 MYH6_7; myosin heavy chain 6/7
K18154 RGS2; regulator of G-protein signaling 2
K18283 PDE2A; cGMP-dependent 3',5'-cyclic phosphodiesterase [EC:3.1.4.17 ]
K19021 PDE3A; cGMP-inhibited 3',5'-cyclic phosphodiesterase A [EC:3.1.4.17 ]
K21289 PIK3CG; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma [EC:2.7.1.153 ]
K21290 PIK3R5_6; phosphoinositide-3-kinase regulatory subunit 5/6
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 ko04270 Vascular smooth muscle contraction
