Entry
Name
cGMP-PKG signaling pathway - Loxodonta africana (African savanna elephant)
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
Loxodonta africana (African savanna elephant) [GN:
lav ]
Gene
100672320 ADRA2A; LOW QUALITY PROTEIN: alpha-2A adrenergic receptor [KO:K04138 ]
100668918 ADRA2C; LOW QUALITY PROTEIN: alpha-2C adrenergic receptor [KO:K04140 ]
100656672 GNAQ; guanine nucleotide-binding protein G(q) subunit alpha isoform X1 [KO:K04634 ]
100676444 GNA12; guanine nucleotide-binding protein subunit alpha-12 [KO:K04346 ]
100664965 GNA13; guanine nucleotide-binding protein subunit alpha-13 [KO:K04639 ]
100661626 PPP3CA; serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform [KO:K04348 ] [EC:3.1.3.16 ]
100664832 PPP3CC; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform isoform X1 [KO:K04348 ] [EC:3.1.3.16 ]
100677352 PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform isoform X1 [KO:K04348 ] [EC:3.1.3.16 ]
100655934 MEF2A; myocyte-specific enhancer factor 2A isoform X1 [KO:K09260 ]
100665046 MEF2B; LOW QUALITY PROTEIN: myocyte-specific enhancer factor 2B [KO:K09261 ]
100656767 MEF2C; myocyte-specific enhancer factor 2C isoform X1 [KO:K04454 ]
100655623 NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 isoform X3 [KO:K04446 ]
100672662 NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 isoform X1 [KO:K17332 ]
100658037 NFATC3; nuclear factor of activated T-cells, cytoplasmic 3 isoform X2 [KO:K17333 ]
100676091 NFATC4; nuclear factor of activated T-cells, cytoplasmic 4 [KO:K17334 ]
100659992 CACNA1D; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851 ]
100674649 CACNA1F; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1F [KO:K04853 ]
100673089 CACNA1S; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857 ]
100656201 KCNMA1; calcium-activated potassium channel subunit alpha-1 isoform X6 [KO:K04936 ]
100675383 KCNU1; LOW QUALITY PROTEIN: potassium channel subfamily U member 1 [KO:K05274 ]
100663278 KCNMB1; calcium-activated potassium channel subunit beta-1 [KO:K04937 ]
100658510 KCNMB2; calcium-activated potassium channel subunit beta-2 [KO:K04938 ]
100657662 KCNMB3; calcium-activated potassium channel subunit beta-3 isoform X3 [KO:K04939 ]
100668504 KCNMB4; calcium-activated potassium channel subunit beta-4 [KO:K04941 ]
100668326 ATP1A3; LOW QUALITY PROTEIN: sodium/potassium-transporting ATPase subunit alpha-3 [KO:K01539 ] [EC:7.2.2.13 ]
100655666 ATP1B3; sodium/potassium-transporting ATPase subunit beta-3 [KO:K01540 ]
100676526 ATP1B1; sodium/potassium-transporting ATPase subunit beta-1 [KO:K01540 ]
100668753 ATP1B2; sodium/potassium-transporting ATPase subunit beta-2 [KO:K01540 ]
111752838 FXYD2; sodium/potassium-transporting ATPase subunit gamma [KO:K01538 ]
100664370 RGS2; LOW QUALITY PROTEIN: regulator of G-protein signaling 2 [KO:K18154 ]
100670617 PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X3 [KO:K05858 ] [EC:3.1.4.11 ]
100672435 PLCB1; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858 ] [EC:3.1.4.11 ]
100668575 PLCB2; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858 ] [EC:3.1.4.11 ]
100663829 PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858 ] [EC:3.1.4.11 ]
100665028 ITPR1; LOW QUALITY PROTEIN: inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958 ]
100659666 ITPR3; LOW QUALITY PROTEIN: inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960 ]
100673922 PPP1R12A; protein phosphatase 1 regulatory subunit 12A isoform X2 [KO:K06270 ]
100673814 PPP1CA; LOW QUALITY PROTEIN: serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269 ] [EC:3.1.3.16 ]
100654047 OPRD1; LOW QUALITY PROTEIN: delta-type opioid receptor [KO:K04213 ]
100666344 GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630 ]
100670234 GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630 ]
100667957 GNAI3; LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630 ]
100660353 LOW QUALITY PROTEIN: insulin receptor substrate 1-like [KO:K17445 ]
100667324 IRS4; LOW QUALITY PROTEIN: insulin receptor substrate 4 [KO:K17446 ]
100673566 PIK3CG; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform [KO:K21289 ] [EC:2.7.1.153 ]
100670067 PIK3R5; phosphoinositide 3-kinase regulatory subunit 5 isoform X1 [KO:K21290 ]
100674744 PIK3R6; phosphoinositide 3-kinase regulatory subunit 6 isoform X1 [KO:K21290 ]
100654973 ADRB1; LOW QUALITY PROTEIN: beta-1 adrenergic receptor [KO:K04141 ]
100658739 KCNJ8; ATP-sensitive inward rectifier potassium channel 8 [KO:K05001 ]
100663098 VDAC1; voltage-dependent anion-selective channel protein 1 [KO:K05862 ]
100667776 VDAC2; voltage-dependent anion-selective channel protein 2 [KO:K15040 ]
100656308 VDAC3; voltage-dependent anion-selective channel protein 3 [KO:K15041 ]
100675162 CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870 ]
100657989 ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450 ]
100662521 ATF4; cyclic AMP-dependent transcription factor ATF-4 isoform X2 [KO:K04374 ]
100653565 CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048 ]
100673694 CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048 ]
100666211 CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048 ]
100670574 CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048 ]
100677344 CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048 ]
100675079 CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047 ]
100666885 ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X2 [KO:K09049 ]
100674787 VASP; vasodilator-stimulated phosphoprotein isoform X1 [KO:K06274 ]
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
lav04270 Vascular smooth muscle contraction
KO pathway
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