KEGG   PATHWAY: bta04022Help
bta04022                    Pathway                                

cGMP-PKG signaling pathway - Bos taurus (cow)
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.
Environmental Information Processing; Signal transduction
BRITE hierarchy
Pathway map
bta04022  cGMP-PKG signaling pathway

Ortholog table
bta_M00694  cGMP signaling [PATH:bta04022]
Other DBs
GO: 0070305
Bos taurus (cow) [GN:bta]
281607  AGTR1; type-1 angiotensin II receptor [KO:K04166]
281749  EDNRA; endothelin-1 receptor precursor [KO:K04197]
281750  EDNRB; endothelin receptor type B precursor [KO:K04198]
282134  ADRA1A; alpha-1A adrenergic receptor [KO:K04135]
407140  ADRA1B; alpha-1B adrenergic receptor [KO:K04136]
539543  ADRA1D; alpha-1D adrenergic receptor [KO:K04137]
282135  ADRA2A; alpha-2A adrenergic receptor [KO:K04138]
516422  ADRA2B; alpha-2B adrenergic receptor [KO:K04139]
407139  ADRA2C; alpha-2C adrenergic receptor [KO:K04140]
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:]
533527  PPP3CC; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform [KO:K04348] [EC:]
790867  PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform [KO:K04348] [EC:]
282321  PPP3R1; calcineurin subunit B type 1 [KO:K06268]
617585  PPP3R2; calcineurin subunit B type 2 [KO:K06268]
407231  MEF2A; myocyte-specific enhancer factor 2A [KO:K09260]
100271851  MEF2B; myocyte-specific enhancer factor 2B [KO:K09261]
512254  MEF2C; myocyte-specific enhancer factor 2C [KO:K04454]
100336730  MEF2D; myocyte-specific enhancer factor 2D [KO:K09262]
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]
533039  SRF; serum response factor [KO:K04378]
327716  GATA4; transcription factor GATA-4 [KO:K09183]
508734  NPPB; natriuretic peptides B precursor [KO:K12335]
281355  NPPA; natriuretic peptides A precursor [KO:K12334]
533048  NPR1; atrial natriuretic peptide receptor 1 precursor [KO:K12323] [EC:]
281356  NPPC; C-type natriuretic peptide precursor [KO:K12336]
281357  NPR2; atrial natriuretic peptide receptor 2 precursor [KO:K12324] [EC:]
282004  PRKG1; cGMP-dependent protein kinase 1 [KO:K07376] [EC:]
533330  PRKG2; cGMP-dependent protein kinase 2 [KO:K19477] [EC:]
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]
282144  ATP1A1; sodium/potassium-transporting ATPase subunit alpha-1 [KO:K01539] [EC:]
515161  ATP1A2; sodium/potassium-transporting ATPase subunit alpha-2 precursor [KO:K01539] [EC:]
537960  ATP1A4; sodium/potassium-transporting ATPase subunit alpha-4 [KO:K01539] [EC:]
282598  ATP1A3; sodium/potassium-transporting ATPase subunit alpha-3 isoform X1 [KO:K01539] [EC:]
282562  ATP1B2; sodium/potassium-transporting ATPase subunit beta-2 [KO:K01540]
510026  ATP1B4; protein ATP1B4 [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]
282641  ATP2B1; plasma membrane calcium-transporting ATPase 1 [KO:K05850] [EC:]
613800  ATP2B2; plasma membrane calcium-transporting ATPase 2 [KO:K05850] [EC:]
504353  ATP2B3; plasma membrane calcium-transporting ATPase 3 [KO:K05850] [EC:]
282146  ATP2B4; plasma membrane calcium-transporting ATPase 4 [KO:K05850] [EC:]
100848920  RGS2; regulator of G-protein signaling 2 [KO:K18154]
513055  RGS2; regulator of G-protein signaling 2 [KO:K18154]
534669  GTF2I; general transcription factor II-I [KO:K03121]
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:]
281985  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:]
515669  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:]
508888  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:]
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]
281918  MRVI1; protein MRVI1 isoform a [KO:K12337]
100125240  PLN; cardiac phospholamban [KO:K05852]
518117  ATP2A1; sarcoplasmic/endoplasmic reticulum calcium ATPase 1 [KO:K05853] [EC:]
512313  ATP2A3; sarcoplasmic/endoplasmic reticulum calcium ATPase 3 [KO:K05853] [EC:]
540568  ATP2A2; sarcoplasmic/endoplasmic reticulum calcium ATPase 2 [KO:K05853] [EC:]
338049  RHOA; transforming protein RhoA precursor [KO:K04513]
785911  ROCK1; rho-associated protein kinase 1 isoform X1 [KO:K04514] [EC:]
282041  ROCK2; rho-associated protein kinase 2 [KO:K17388] [EC:]
538606  PPP1R12A; protein phosphatase 1 regulatory subunit 12A [KO:K06270]
282318  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:]
516175  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:]
538829  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:]
326597  CALM; calmodulin [KO:K02183]
520277  CALM3; calmodulin [KO:K02183]
617095  CALM1; calmodulin [KO:K02183]
520404  CALML5; calmodulin-like protein 5 [KO:K02183]
100297344  CALM2; calmodulin [KO:K02183]
617412  CALML6; LOW QUALITY PROTEIN: calmodulin-like protein 6 [KO:K02183]
104973792  calcium-dependent protein kinase 10 [KO:K02183]
539277  CALML4; calmodulin-like protein 4 [KO:K02183]
338037  MYLK; myosin light chain kinase, smooth muscle [KO:K00907] [EC:]
533378  MYLK2; myosin light chain kinase 2, skeletal/cardiac muscle [KO:K00907] [EC:]
526379  MYLK3; myosin light chain kinase 3 isoform X2 [KO:K00907] [EC:]
518025  MYLK4; myosin light chain kinase family member 4 isoform X1 [KO:K00907] [EC:]
505964  MYL9; myosin regulatory light polypeptide 9 [KO:K12755]
281700  CNGA1; cGMP-gated cation channel alpha-1 [KO:K04948]
281601  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:]
510708  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:]
535603  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:]
788151  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:]
505740  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:]
509936  ADCY6; adenylate cyclase type 6 [KO:K08046] [EC:]
281603  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:]
535017  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:]
525482  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:]
281971  PDE2A; cGMP-dependent 3',5'-cyclic phosphodiesterase isoform PDE2A1 [KO:K18283] [EC:]
536636  PDE3A; LOW QUALITY PROTEIN: cGMP-inhibited 3',5'-cyclic phosphodiesterase A [KO:K19021] [EC:]
533323  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:]
281972  PDE5A; cGMP-specific 3',5'-cyclic phosphodiesterase [KO:K13762] [EC:]
613600  GUCY1A2; guanylate cyclase soluble subunit alpha-2 [KO:K12318] [EC:]
281216  GUCY1A1; guanylate cyclase soluble subunit alpha-1 [KO:K12318] [EC:]
282433  GUCY1B1; guanylate cyclase soluble subunit beta-1 [KO:K12319] [EC:]
280833  KNG1; kininogen-2 isoform II precursor [KO:K03898]
538896  BDKRB2; B2 bradykinin receptor [KO:K03916]
781956  OPRD1; delta-type opioid receptor [KO:K04213]
282133  ADORA1; adenosine receptor A1 [KO:K04265]
780806  ADORA3; adenosine receptor A3 isoform 1 [KO:K04268]
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]
280829  INS; insulin preproprotein [KO:K04526]
408017  INSR; insulin receptor isoform X1 [KO:K04527] [EC:]
538598  IRS1; insulin receptor substrate 1 [KO:K16172]
100300012  IRS2; insulin receptor substrate 2 [KO:K07187]
107131843  insulin receptor substrate 1-like isoform X1 [KO:K17445]
514607  IRS4; insulin receptor substrate 4 [KO:K17446]
530001  PIK3CG; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform [KO:K21289] [EC:]
614838  PIK3R5; phosphoinositide 3-kinase regulatory subunit 5 isoform X3 [KO:K21290]
515621  PIK3R6; phosphoinositide 3-kinase regulatory subunit 6 [KO:K21290]
534923  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:]
280991  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:]
100137872  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:]
287024  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:]
281604  ADRB1; beta-1 adrenergic receptor [KO:K04141]
281605  ADRB2; beta-2 adrenergic receptor [KO:K04142]
281606  ADRB3; beta-3 adrenergic receptor [KO:K04143]
507041  PRKCE; protein kinase C epsilon type [KO:K18050] [EC:]
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]
282478  SLC25A4; ADP/ATP translocase 1 [KO:K05863]
282479  SLC25A5; ADP/ATP translocase 2 [KO:K05863]
282480  SLC25A6; ADP/ATP translocase 3 [KO:K05863]
541168  SLC25A31; ADP/ATP translocase 4 [KO:K05863]
787122  ADP/ATP translocase 1 [KO:K05863]
414346  PPIF; peptidyl-prolyl cis-trans isomerase F, mitochondrial precursor [KO:K09565] [EC:]
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]
521196  RAF1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:]
533199  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
510434  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:]
327672  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
531391  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
C00020  AMP
C00027  Hydrogen peroxide
C00076  Calcium cation
C00144  GMP
C00212  Adenosine
C00238  Potassium cation
C00533  Nitric oxide
C00575  3',5'-Cyclic AMP
C00942  3',5'-Cyclic GMP
C01245  D-myo-Inositol 1,4,5-trisphosphate
Francis SH, Busch JL, Corbin JD, Sibley D
cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action.
Pharmacol Rev 62:525-63 (2010)
Feil R, Kemp-Harper B
cGMP signalling: from bench to bedside. Conference on cGMP generators, effectors and therapeutic implications.
EMBO Rep 7:149-53 (2006)
Takimoto E
Cyclic GMP-dependent signaling in cardiac myocytes.
Circ J 76:1819-25 (2012)
Hofmann F, Feil R, Kleppisch T, Schlossmann J
Function of cGMP-dependent protein kinases as revealed by gene deletion.
Physiol Rev 86:1-23 (2006)
Kuebler WM
The Janus-faced regulation of endothelial permeability by cyclic GMP.
Am J Physiol Lung Cell Mol Physiol 301:L157-60 (2011)
Schlossmann J, Desch M
IRAG and novel PKG targeting in the cardiovascular system.
Am J Physiol Heart Circ Physiol 301:H672-82 (2011)
Murthy KS
Signaling for contraction and relaxation in smooth muscle of the gut.
Annu Rev Physiol 68:345-74 (2006)
Sanders KM, Koh SD, Ro S, Ward SM
Regulation of gastrointestinal motility--insights from smooth muscle biology.
Nat Rev Gastroenterol Hepatol 9:633-45 (2012)
Gao Y
The multiple actions of NO.
Pflugers Arch 459:829-39 (2010)
Wang X, Robinson PJ
Cyclic GMP-dependent protein kinase and cellular signaling in the nervous system.
J Neurochem 68:443-56 (1997)
Tsai EJ, Kass DA
Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics.
Pharmacol Ther 122:216-38 (2009)
Villanueva C, Giulivi C
Subcellular and cellular locations of nitric oxide synthase isoforms as determinants of health and disease.
Free Radic Biol Med 49:307-16 (2010)
Schlossmann J, Hofmann F
cGMP-dependent protein kinases in drug discovery.
Drug Discov Today 10:627-34 (2005)
Kass DA, Champion HC, Beavo JA
Phosphodiesterase type 5: expanding roles in cardiovascular regulation.
Circ Res 101:1084-95 (2007)
Uckert S, Hedlund P, Andersson KE, Truss MC, Jonas U, Stief CG
Update on phosphodiesterase (PDE) isoenzymes as pharmacologic targets in urology: present and future.
Eur Urol 50:1194-207; discussion 1207 (2006)
Yan C, Kim D, Aizawa T, Berk BC
Functional interplay between angiotensin II and nitric oxide: cyclic GMP as a key mediator.
Arterioscler Thromb Vasc Biol 23:26-36 (2003)
McKinsey TA, Kass DA
Small-molecule therapies for cardiac hypertrophy: moving beneath the cell surface.
Nat Rev Drug Discov 6:617-35 (2007)
Koitabashi N, Aiba T, Hesketh GG, Rowell J, Zhang M, Takimoto E, Tomaselli GF, Kass DA
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.
J Mol Cell Cardiol 48:713-24 (2010)
Costa AD, Pierre SV, Cohen MV, Downey JM, Garlid KD
cGMP signalling in pre- and post-conditioning: the role of mitochondria.
Cardiovasc Res 77:344-52 (2008)
Boengler K, Schulz R, Heusch G
Loss of cardioprotection with ageing.
Cardiovasc Res 83:247-61 (2009)
Gao Y, Portugal AD, Liu J, Negash S, Zhou W, Tian J, Xiang R, Longo LD, Raj JU
Preservation of cGMP-induced relaxation of pulmonary veins of fetal lambs exposed to chronic high altitude hypoxia: role of PKG and Rho kinase.
Am J Physiol Lung Cell Mol Physiol 295:L889-96 (2008)
Li Z, Xi X, Du X
A mitogen-activated protein kinase-dependent signaling pathway in the activation of platelet integrin alpha IIbbeta3.
J Biol Chem 276:42226-32 (2001)
Xie J, Cha SK, An SW, Kuro-O M, Birnbaumer L, Huang CL
Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart.
Nat Commun 3:1238 (2012)
KO pathway

DBGET integrated database retrieval system