Entry
Name
cGMP-PKG signaling pathway - Homo sapiens (human)
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
Drug
D00227 Aminophylline (USP/INN)
D00255 Carvedilol (JP18/USP/INN)
D00281 Clonidine (JAN/USP/INN)
D00302 Dipyridamole (JP18/USP/INN)
D00417 Milrinone (JAN/USP/INN)
D00598 Betaxolol hydrochloride (JP18/USP)
D00599 Carteolol hydrochloride (JP18/USP)
D00600 Labetalol hydrochloride (JP18/USP)
D00603 Timolol maleate (JP18/USP)
D00604 Clonidine hydrochloride (JP18/USP)
D00606 Guanfacine hydrochloride (JAN/USP)
D00610 Terazosin hydrochloride (USP)
D00631 Bepridil hydrochloride (USAN)
D00632 Dobutamine hydrochloride (JP18/USP)
D00634 Bisoprolol fumarate (JP18/USP)
D00636 Amiodarone hydrochloride (JP18/USP)
D00680 Methylergonovine maleate (USP)
D00996 Epinephrine hydrochloride (JAN)
D01024 Tamsulosin hydrochloride (JP18/USP)
D01163 Ergonovine maleate (USP)
D01238 Bucladesine sodium (JAN)
D01469 Amosulalol hydrochloride (JP18)
D01573 Etilefrine hydrochloride (JP18)
D01692 Alfuzosin hydrochloride (JAN/USAN)
D01712 Theophylline sodium acetate (JAN)
D01771 Proxyphylline (JAN/INN)
D01810 Nicorandil (JP18/USAN/INN)
D01830 Arotinolol hydrochloride (JP18)
D01840 Fasudil hydrochloride (JAN)
D01896 Cilostazol (JP18/USP/INN)
D01958 Indenolol hydrochloride (JP18)
D02084 Inamrinone ethylenelactate
D02149 Epinephrine bitartrate (JAN/USP)
D02218 Papaverine hydrochloride (JP18/USP)
D02229 Sildenafil citrate (JAN/USP)
D02342 Bisoprolol (JAN/USAN/INN)
D02731 Vardenafil dihydrochoride (USAN)
D02976 Arbutamine hydrochloride (USAN)
D03051 Bamifylline hydrochloride (USAN)
D03115 Fasudil hydrochloride hydrate (JAN)
D03177 Bunolol hydrochloride (USAN)
D03260 Vardenafil hydrochloride hydrate (JAN)
D03415 Carvedilol phosphate (USAN)
D03892 Dopexamine hydrochloride (USAN)
D04508 Imazodan hydrochloride (USAN)
D04510 Imciromab pentetate (USAN)
D04628 Isomazole hydrochloride (USAN)
D04710 Levobetaxolol hydrochloride (USAN)
D04720 Levosimendan (USAN/INN)
D04751 Lixazinone sulfate (USAN)
D05429 Aminophylline hydrate (JP18)
D05688 Racepinephrine (USP/INN)
D05689 Racepinephrine hydrochloride (USP)
D05879 Solabegron hydrochloride (USAN)
D06104 Theophylline sodium glycinate (USP)
D06562 Bedoradrine sulfate (USAN)
D06671 Yohimbine hydrochloride (USP)
D07560 Adrenalone hydrochloride
D08207 Methylergometrine (INN)
D09989 Vardenafil hydrochloride (USP)
D10971 Piclidenoson (USAN/INN)
D11031 Netarsudil mesylate (USAN)
D11321 Vatinoxan hydrochloride (USAN)
D11585 Terazosin hydrochloride anhydrous
D11630 Aminophylline dihydrate
D11743 Ensifentrine (USAN/INN)
D11975 Centhaquine citrate (USAN)
D12265 Mavacamten (JAN/USAN/INN)
D12934 Dibutepinephrine (USAN/INN)
D12935 Dibutepinephrine hydrochloride (USAN)
Other DBs
Organism
Homo sapiens (human) [GN:
hsa ]
Gene
185 AGTR1; angiotensin II receptor type 1 [KO:K04166 ]
1909 EDNRA; endothelin receptor type A [KO:K04197 ]
1910 EDNRB; endothelin receptor type B [KO:K04198 ]
148 ADRA1A; adrenoceptor alpha 1A [KO:K04135 ]
147 ADRA1B; adrenoceptor alpha 1B [KO:K04136 ]
146 ADRA1D; adrenoceptor alpha 1D [KO:K04137 ]
150 ADRA2A; adrenoceptor alpha 2A [KO:K04138 ]
151 ADRA2B; adrenoceptor alpha 2B [KO:K04139 ]
152 ADRA2C; adrenoceptor alpha 2C [KO:K04140 ]
2767 GNA11; G protein subunit alpha 11 [KO:K04635 ]
2768 GNA12; G protein subunit alpha 12 [KO:K04346 ]
7225 TRPC6; transient receptor potential cation channel subfamily C member 6 [KO:K04969 ]
5534 PPP3R1; protein phosphatase 3 regulatory subunit B, alpha [KO:K06268 ]
5535 PPP3R2; protein phosphatase 3 regulatory subunit B, beta [KO:K06268 ]
4205 MEF2A; myocyte enhancer factor 2A [KO:K09260 ]
4207 BORCS8-MEF2B; BORCS8-MEF2B readthrough [KO:K09261 ]
4208 MEF2C; myocyte enhancer factor 2C [KO:K04454 ]
4209 MEF2D; myocyte enhancer factor 2D [KO:K09262 ]
4772 NFATC1; nuclear factor of activated T cells 1 [KO:K04446 ]
4773 NFATC2; nuclear factor of activated T cells 2 [KO:K17332 ]
4775 NFATC3; nuclear factor of activated T cells 3 [KO:K17333 ]
4776 NFATC4; nuclear factor of activated T cells 4 [KO:K17334 ]
775 CACNA1C; calcium voltage-gated channel subunit alpha1 C [KO:K04850 ]
776 CACNA1D; calcium voltage-gated channel subunit alpha1 D [KO:K04851 ]
778 CACNA1F; calcium voltage-gated channel subunit alpha1 F [KO:K04853 ]
779 CACNA1S; calcium voltage-gated channel subunit alpha1 S [KO:K04857 ]
3778 KCNMA1; potassium calcium-activated channel subfamily M alpha 1 [KO:K04936 ]
157855 KCNU1; potassium calcium-activated channel subfamily U member 1 [KO:K05274 ]
3779 KCNMB1; potassium calcium-activated channel subfamily M regulatory beta subunit 1 [KO:K04937 ]
10242 KCNMB2; potassium calcium-activated channel subfamily M regulatory beta subunit 2 [KO:K04938 ]
27094 KCNMB3; potassium calcium-activated channel subfamily M regulatory beta subunit 3 [KO:K04939 ]
27345 KCNMB4; potassium calcium-activated channel subfamily M regulatory beta subunit 4 [KO:K04941 ]
6546 SLC8A1; solute carrier family 8 member A1 [KO:K05849 ]
6543 SLC8A2; solute carrier family 8 member A2 [KO:K05849 ]
6547 SLC8A3; solute carrier family 8 member A3 [KO:K05849 ]
23439 ATP1B4; ATPase Na+/K+ transporting family member beta 4 [KO:K01540 ]
481 ATP1B1; ATPase Na+/K+ transporting subunit beta 1 [KO:K01540 ]
482 ATP1B2; ATPase Na+/K+ transporting subunit beta 2 [KO:K01540 ]
483 ATP1B3; ATPase Na+/K+ transporting subunit beta 3 [KO:K01540 ]
486 FXYD2; FXYD domain containing ion transport regulator 2 [KO:K01538 ]
5997 RGS2; regulator of G protein signaling 2 [KO:K18154 ]
2969 GTF2I; general transcription factor IIi [KO:K03121 ]
3708 ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958 ]
3709 ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959 ]
3710 ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960 ]
10335 IRAG1; inositol 1,4,5-triphosphate receptor associated 1 [KO:K12337 ]
487 ATP2A1; ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 1 [KO:K05853 ] [EC:7.2.2.10 ]
489 ATP2A3; ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 3 [KO:K05853 ] [EC:7.2.2.10 ]
488 ATP2A2; ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2 [KO:K05853 ] [EC:7.2.2.10 ]
387 RHOA; ras homolog family member A [KO:K04513 ]
4659 PPP1R12A; protein phosphatase 1 regulatory subunit 12A [KO:K06270 ]
1259 CNGA1; cyclic nucleotide gated channel subunit alpha 1 [KO:K04948 ]
1258 CNGB1; cyclic nucleotide gated channel subunit beta 1 [KO:K04952 ]
624 BDKRB2; bradykinin receptor B2 [KO:K03916 ]
134 ADORA1; adenosine A1 receptor [KO:K04265 ]
140 ADORA3; adenosine A3 receptor [KO:K04268 ]
2770 GNAI1; G protein subunit alpha i1 [KO:K04630 ]
2773 GNAI3; G protein subunit alpha i3 [KO:K04630 ]
2771 GNAI2; G protein subunit alpha i2 [KO:K04630 ]
3667 IRS1; insulin receptor substrate 1 [KO:K16172 ]
8660 IRS2; insulin receptor substrate 2 [KO:K07187 ]
8471 IRS4; insulin receptor substrate 4 [KO:K17446 ]
5294 PIK3CG; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma [KO:K21289 ] [EC:2.7.1.153 ]
23533 PIK3R5; phosphoinositide-3-kinase regulatory subunit 5 [KO:K21290 ]
146850 PIK3R6; phosphoinositide-3-kinase regulatory subunit 6 [KO:K21290 ]
3764 KCNJ8; potassium inwardly rectifying channel subfamily J member 8 [KO:K05001 ]
7416 VDAC1; voltage dependent anion channel 1 [KO:K05862 ]
7417 VDAC2; voltage dependent anion channel 2 [KO:K15040 ]
7419 VDAC3; voltage dependent anion channel 3 [KO:K15041 ]
291 SLC25A4; solute carrier family 25 member 4 [KO:K05863 ]
292 SLC25A5; solute carrier family 25 member 5 [KO:K05863 ]
293 SLC25A6; solute carrier family 25 member 6 [KO:K05863 ]
83447 SLC25A31; solute carrier family 25 member 31 [KO:K05863 ]
1385 CREB1; cAMP responsive element binding protein 1 [KO:K05870 ]
1386 ATF2; activating transcription factor 2 [KO:K04450 ]
468 ATF4; activating transcription factor 4 [KO:K04374 ]
10488 CREB3; cAMP responsive element binding protein 3 [KO:K09048 ]
90993 CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048 ]
64764 CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048 ]
84699 CREB3L3; cAMP responsive element binding protein 3 like 3 [KO:K09048 ]
148327 CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048 ]
9586 CREB5; cAMP responsive element binding protein 5 [KO:K09047 ]
1388 ATF6B; activating transcription factor 6 beta [KO:K09049 ]
572 BAD; BCL2 associated agonist of cell death [KO:K02158 ]
7408 VASP; vasodilator stimulated phosphoprotein [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
hsa04270 Vascular smooth muscle contraction
KO pathway