KEGG PATHWAY: ko04022

PATHWAY: ko04022

Entry

ko04022                     Pathway

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 transduction

Pathway map

ko04022

cGMP-PKG signaling pathway

Other DBs

GO:

0070305

Orthology

K04166

angiotensin II receptor type 1

K04197

endothelin receptor type A

K04198

endothelin receptor type B

K04135

adrenergic receptor alpha-1A

K04136

adrenergic receptor alpha-1B

K04137

adrenergic receptor alpha-1D

K04138

adrenergic receptor alpha-2A

K04139

adrenergic receptor alpha-2B

K04140

adrenergic receptor alpha-2C

K04634

guanine nucleotide-binding protein G(q) subunit alpha

K04635

guanine nucleotide-binding protein subunit alpha-11

K04346

guanine nucleotide-binding protein subunit alpha-12

K04639

guanine nucleotide-binding protein subunit alpha-13

K04969

transient receptor potential cation channel subfamily C member 6

K04348

serine/threonine-protein phosphatase 2B catalytic subunit [EC:3.1.3.16]

K06268

serine/threonine-protein phosphatase 2B regulatory subunit

K09260

MADS-box transcription enhancer factor 2A

K09261

MADS-box transcription enhancer factor 2B

K04454

MADS-box transcription enhancer factor 2C

K09262

MADS-box transcription enhancer factor 2D

K04446

nuclear factor of activated T-cells, cytoplasmic 1

K17332

nuclear factor of activated T-cells, cytoplasmic 2

K17333

nuclear factor of activated T-cells, cytoplasmic 3

K17334

nuclear factor of activated T-cells, cytoplasmic 4

K04378

serum response factor

K09183

GATA-binding protein 4

K17751

myosin heavy chain 6/7

K12335

natriuretic peptide B

K12334

natriuretic peptide A

K12323

atrial natriuretic peptide receptor A [EC:4.6.1.2]

K12336

natriuretic peptide C

K12324

atrial natriuretic peptide receptor B [EC:4.6.1.2]

K07376

cGMP-dependent protein kinase 1 [EC:2.7.11.12]

K19477

cGMP-dependent protein kinase 2 [EC:2.7.11.12]

K04850

voltage-dependent calcium channel L type alpha-1C

K04851

voltage-dependent calcium channel L type alpha-1D

K04853

voltage-dependent calcium channel L type alpha-1F

K04857

voltage-dependent calcium channel L type alpha-1S

K04936

potassium large conductance calcium-activated channel subfamily M alpha member 1

K05274

potassium large conductance calcium-activated channel subfamily M alpha member 3

K04937

potassium large conductance calcium-activated channel subfamily M beta member 1

K04938

potassium large conductance calcium-activated channel subfamily M beta member 2

K04939

potassium large conductance calcium-activated channel subfamily M beta member 3

K04941

potassium large conductance calcium-activated channel subfamily M beta member 4

K05849

solute carrier family 8 (sodium/calcium exchanger)

K01539

sodium/potassium-transporting ATPase subunit alpha [EC:7.2.2.13]

K01540

sodium/potassium-transporting ATPase subunit beta

K01538

sodium/potassium-transporting ATPase subunit gamma (FXYD domain-containing ion transport regulator 2)

K05850

P-type Ca2+ transporter type 2B [EC:7.2.2.10]

K18154

regulator of G-protein signaling 2

K03121

transcription initiation factor TFII-I

K05858

phosphatidylinositol phospholipase C, beta [EC:3.1.4.11]

K04958

inositol 1,4,5-triphosphate receptor type 1

K04959

inositol 1,4,5-triphosphate receptor type 2

K04960

inositol 1,4,5-triphosphate receptor type 3

K12337

inositol 1,4,5-triphosphate receptor-associated cGMP kinase substrate

K05852

phospholamban

K05853

P-type Ca2+ transporter type 2A [EC:7.2.2.10]

K04513

Ras homolog gene family, member A

K04514

Rho-associated protein kinase 1 [EC:2.7.11.1]

K17388

Rho-associated protein kinase 2 [EC:2.7.11.1]

K06270

protein phosphatase 1 regulatory subunit 12A

K06269

serine/threonine-protein phosphatase PP1 catalytic subunit [EC:3.1.3.16]

K02183

calmodulin

K00907

myosin-light-chain kinase [EC:2.7.11.18]

K12755

myosin regulatory light chain 9

K04948

cyclic nucleotide gated channel alpha 1

K04952

cyclic nucleotide gated channel beta 1

K08041

adenylate cyclase 1 [EC:4.6.1.1]

K08042

adenylate cyclase 2 [EC:4.6.1.1]

K08043

adenylate cyclase 3 [EC:4.6.1.1]

K08044

adenylate cyclase 4 [EC:4.6.1.1]

K08045

adenylate cyclase 5 [EC:4.6.1.1]

K08046

adenylate cyclase 6 [EC:4.6.1.1]

K08047

adenylate cyclase 7 [EC:4.6.1.1]

K08048

adenylate cyclase 8 [EC:4.6.1.1]

K08049

adenylate cyclase 9 [EC:4.6.1.1]

K18283

cGMP-dependent 3',5'-cyclic phosphodiesterase [EC:3.1.4.17]

K19021

cGMP-inhibited 3',5'-cyclic phosphodiesterase A [EC:3.1.4.17]

K13296

cGMP-inhibited 3',5'-cyclic phosphodiesterase B [EC:3.1.4.17]

K13762

cGMP-specific 3',5'-cyclic phosphodiesterase [EC:3.1.4.35]

K12318

guanylate cyclase soluble subunit alpha [EC:4.6.1.2]

K12319

guanylate cyclase soluble subunit beta [EC:4.6.1.2]

K03898

kininogen

K03916

bradykinin receptor B2

K04213

delta-type opioid receptor

K04265

adenosine receptor A1

K04268

adenosine receptor A3

K04630

guanine nucleotide-binding protein G(i) subunit alpha

K04526

insulin

K04527

insulin receptor [EC:2.7.10.1]

K16172

insulin receptor substrate 1

K07187

insulin receptor substrate 2

K17445

insulin receptor substrate 3

K17446

insulin receptor substrate 4

K21289

phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma [EC:2.7.1.153]

K21290

phosphoinositide-3-kinase regulatory subunit 5/6

K04456

RAC serine/threonine-protein kinase [EC:2.7.11.1]

K13242

nitric-oxide synthase, endothelial [EC:1.14.13.39]

K04141

adrenergic receptor beta-1

K04142

adrenergic receptor beta-2

K04143

adrenergic receptor beta-3

K18050

novel protein kinase C epsilon type [EC:2.7.11.13]

K05001

potassium inwardly-rectifying channel subfamily J member 8

K05862

voltage-dependent anion channel protein 1

K15040

voltage-dependent anion channel protein 2

K15041

voltage-dependent anion channel protein 3

K05863

solute carrier family 25 (mitochondrial adenine nucleotide translocator), member 4/5/6/31

K09565

peptidyl-prolyl isomerase F (cyclophilin D) [EC:5.2.1.8]

K05870

cyclic AMP-responsive element-binding protein 1

K04450

cyclic AMP-dependent transcription factor ATF-2

K04374

cyclic AMP-dependent transcription factor ATF-4

K09048

cyclic AMP-responsive element-binding protein 3

K09047

cyclic AMP-responsive element-binding protein 5

K09049

cyclic AMP-dependent transcription factor ATF-6 beta

K02158

Bcl-2-antagonist of cell death

K06274

vasodilator-stimulated phosphoprotein

K04366

RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]

K04368

mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]

K04369

mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]

K04371

mitogen-activated protein kinase 1/3 [EC:2.7.11.24]

Compound

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

Reference

PMID:20716671

Authors

Francis SH, Busch JL, Corbin JD, Sibley D

Title

cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action.

Journal

Pharmacol Rev 62:525-63 (2010)
DOI:10.1124/pr.110.002907

Reference

PMID:16439998

Authors

Feil R, Kemp-Harper B

Title

cGMP signalling: from bench to bedside. Conference on cGMP generators, effectors and therapeutic implications.

Journal

EMBO Rep 7:149-53 (2006)
DOI:10.1038/sj.embor.7400627

Reference

PMID:22785374

Authors

Takimoto E

Title

Cyclic GMP-dependent signaling in cardiac myocytes.

Journal

Circ J 76:1819-25 (2012)
DOI:10.1253/circj.CJ-12-0664

Reference

PMID:16371594

Authors

Hofmann F, Feil R, Kleppisch T, Schlossmann J

Title

Function of cGMP-dependent protein kinases as revealed by gene deletion.

Journal

Physiol Rev 86:1-23 (2006)
DOI:10.1152/physrev.00015.2005

Reference

PMID:21685243

Authors

Kuebler WM

Title

The Janus-faced regulation of endothelial permeability by cyclic GMP.

Journal

Am J Physiol Lung Cell Mol Physiol 301:L157-60 (2011)
DOI:10.1152/ajplung.00192.2011

Reference

PMID:21666108

Authors

Schlossmann J, Desch M

Title

IRAG and novel PKG targeting in the cardiovascular system.

Journal

Am J Physiol Heart Circ Physiol 301:H672-82 (2011)
DOI:10.1152/ajpheart.00198.2011

Reference

PMID:16460276

Authors

Murthy KS

Title

Signaling for contraction and relaxation in smooth muscle of the gut.

Journal

Annu Rev Physiol 68:345-74 (2006)
DOI:10.1146/annurev.physiol.68.040504.094707

Reference

PMID:22965426

Authors

Sanders KM, Koh SD, Ro S, Ward SM

Title

Regulation of gastrointestinal motility--insights from smooth muscle biology.

Journal

Nat Rev Gastroenterol Hepatol 9:633-45 (2012)
DOI:10.1038/nrgastro.2012.168

Reference

PMID:20024580

Authors

Gao Y

Title

The multiple actions of NO.

Journal

Pflugers Arch 459:829-39 (2010)
DOI:10.1007/s00424-009-0773-9

Reference

PMID:9003029

Authors

Wang X, Robinson PJ

Title

Cyclic GMP-dependent protein kinase and cellular signaling in the nervous system.

Journal

J Neurochem 68:443-56 (1997)
DOI:10.1046/j.1471-4159.1997.68020443.x

Reference

PMID:19306895

Authors

Tsai EJ, Kass DA

Title

Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics.

Journal

Pharmacol Ther 122:216-38 (2009)
DOI:10.1016/j.pharmthera.2009.02.009

Reference

PMID:20388537

Authors

Villanueva C, Giulivi C

Title

Subcellular and cellular locations of nitric oxide synthase isoforms as determinants of health and disease.

Journal

Free Radic Biol Med 49:307-16 (2010)
DOI:10.1016/j.freeradbiomed.2010.04.004

Reference

PMID:15894227

Authors

Schlossmann J, Hofmann F

Title

cGMP-dependent protein kinases in drug discovery.

Journal

Drug Discov Today 10:627-34 (2005)
DOI:10.1016/S1359-6446(05)03406-9

Reference

PMID:18040025

Authors

Kass DA, Champion HC, Beavo JA

Title

Phosphodiesterase type 5: expanding roles in cardiovascular regulation.

Journal

Circ Res 101:1084-95 (2007)
DOI:10.1161/CIRCRESAHA.107.162511

Reference

PMID:16815627

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

Eur Urol 50:1194-207; discussion 1207 (2006)
DOI:10.1016/j.eururo.2006.05.025

Reference

PMID:12524221

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

Arterioscler Thromb Vasc Biol 23:26-36 (2003)
DOI:10.1161/01.ATV.0000046231.17365.9D

Reference

PMID:17643091

Authors

McKinsey TA, Kass DA

Title

Small-molecule therapies for cardiac hypertrophy: moving beneath the cell surface.

Journal

Nat Rev Drug Discov 6:617-35 (2007)
DOI:10.1038/nrd2193

Reference

PMID:19961855

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

J Mol Cell Cardiol 48:713-24 (2010)
DOI:10.1016/j.yjmcc.2009.11.015

Reference

PMID:18006449

Authors

Costa AD, Pierre SV, Cohen MV, Downey JM, Garlid KD

Title

cGMP signalling in pre- and post-conditioning: the role of mitochondria.

Journal

Cardiovasc Res 77:344-52 (2008)
DOI:10.1093/cvr/cvm050

Reference

PMID:19176601