KEGG   PATHWAY: ko04261Help
Entry
ko04261                     Pathway                                

Name
Adrenergic signaling in cardiomyocytes
Description
Cardiac myocytes express at least six subtypes of adrenergic receptor (AR) which include three subtypes of beta-AR (beta-1, beta-2, beta-3) and three subtypes of the alpha-1-AR (alpha-1A, alpha-1B, and alpha-1C). In the human heart the beta-1-AR is the pre- dominate receptor. Acute sympathetic stimulation of cardiac beta-1-ARs induces positive inotropic and chronotropic effects, the most effective mechanism to acutely increase output of the heart, by coupling to Gs, formation of cAMP by adenylyl cyclase (AC), and PKA- dependent phosphorylation of various target proteins (e.g., ryanodine receptor [RyR]; phospholamban [PLB], troponin I [TnI], and the L-type Ca2+ channel [LTCC]). Chronic beta-1-AR stimulation is detrimental and induces cardiomyocyte hypertrophy and apoptosis. beta-2-AR coupled to Gs exerts a proapoptotic action as well as beta-1-AR, while beta-2-AR coupled to Gi exerts an antiapoptotic action.
Class
Organismal Systems; Circulatory system
BRITE hierarchy
Pathway map
ko04261  Adrenergic signaling in cardiomyocytes
ko04261

Ortholog table
Disease
H00720  Long QT syndrome
H00731  Atrial fibrillation
H00773  Autosomal dominant mental retardation
H01019  Catecholaminergic polymorphic ventricular tachycardia
H02091  Jervell and Lange-Nielsen syndrome
Other DBs
GO: 0001997
Orthology
K04141  adrenergic receptor beta-1
K04142  adrenergic receptor beta-2
K04632  guanine nucleotide-binding protein G(s) subunit alpha
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]
K04345  protein kinase A [EC:2.7.11.11]
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)
K05742  solute carrier family 9 (sodium/hydrogen exchanger), member 1
K04926  potassium voltage-gated channel KQT-like subfamily member 1
K04894  potassium voltage-gated channel Isk-related subfamily E member 1
K05850  P-type Ca2+ transporter type 2B [EC:7.2.2.10]
K05849  solute carrier family 8 (sodium/calcium exchanger)
K04838  voltage-gated sodium channel type V alpha
K04839  voltage-gated sodium channel type VII alpha
K04845  voltage-gated sodium channel type I beta
K04848  voltage-gated sodium channel type IV beta
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
K04862  voltage-dependent calcium channel beta-1
K04863  voltage-dependent calcium channel beta-2
K04864  voltage-dependent calcium channel beta-3
K04865  voltage-dependent calcium channel beta-4
K04858  voltage-dependent calcium channel alpha-2/delta-1
K04859  voltage-dependent calcium channel alpha-2/delta-2
K04860  voltage-dependent calcium channel alpha-2/delta-3
K04861  voltage-dependent calcium channel alpha-2/delta-4
K04866  voltage-dependent calcium channel gamma-1
K04867  voltage-dependent calcium channel gamma-2
K04868  voltage-dependent calcium channel gamma-3
K04869  voltage-dependent calcium channel gamma-4
K04870  voltage-dependent calcium channel gamma-5
K04871  voltage-dependent calcium channel gamma-6
K04872  voltage-dependent calcium channel gamma-7
K04873  voltage-dependent calcium channel gamma-8
K02183  calmodulin
K04515  calcium/calmodulin-dependent protein kinase (CaM kinase) II [EC:2.7.11.17]
K04962  ryanodine receptor 2
K04382  serine/threonine-protein phosphatase 2A catalytic subunit [EC:3.1.3.16]
K03456  serine/threonine-protein phosphatase 2A regulatory subunit A
K04354  serine/threonine-protein phosphatase 2A regulatory subunit B
K11583  serine/threonine-protein phosphatase 2A regulatory subunit B''
K11584  serine/threonine-protein phosphatase 2A regulatory subunit B'
K06269  serine/threonine-protein phosphatase PP1 catalytic subunit [EC:3.1.3.16]
K05865  troponin C, slow skeletal and cardiac muscles
K12044  troponin I, cardiac muscle
K12045  troponin T, cardiac muscle
K10373  tropomyosin 1
K10374  tropomyosin 2
K09290  tropomyosin 3
K10375  tropomyosin 4
K12314  actin, alpha cardiac muscle
K17751  myosin heavy chain 6/7
K10351  myosin regulatory light chain 2
K12749  myosin light chain 3
K12750  myosin light chain 4
K05852  phospholamban
K05853  P-type Ca2+ transporter type 2A [EC:7.2.2.10]
K09821  angiotensinogen
K04166  angiotensin II receptor type 1
K04167  angiotensin II receptor type 2
K04135  adrenergic receptor alpha-1A
K04136  adrenergic receptor alpha-1B
K04137  adrenergic receptor alpha-1D
K04634  guanine nucleotide-binding protein G(q) subunit alpha
K05858  phosphatidylinositol phospholipase C, beta [EC:3.1.4.11]
K02677  classical protein kinase C alpha type [EC:2.7.11.13]
K08050  protein phosphatase 1 regulatory subunit 1A
K04371  mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K04445  ribosomal protein S6 kinase alpha-5 [EC:2.7.11.1]
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
K09052  cAMP response element modulator
K02161  apoptosis regulator Bcl-2
K08014  Rap guanine nucleotide exchange factor 3
K04351  Rap guanine nucleotide exchange factor 4
K04441  p38 MAP kinase [EC:2.7.11.24]
K04630  guanine nucleotide-binding protein G(i) subunit alpha
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]
Compound
C00076  Calcium cation
C00080  H+
C00165  Diacylglycerol
C00238  Potassium cation
C00547  L-Noradrenaline
C00575  3',5'-Cyclic AMP
C00788  L-Adrenaline
C01245  D-myo-Inositol 1,4,5-trisphosphate
C01330  Sodium cation
C07056  Isoproterenol
Reference
  Authors
Grimm M, Brown JH
  Title
Beta-adrenergic receptor signaling in the heart: role of CaMKII.
  Journal
J Mol Cell Cardiol 48:322-30 (2010)
DOI:10.1016/j.yjmcc.2009.10.016
Reference
  Authors
Yang JH, Saucerman JJ
  Title
Computational models reduce complexity and accelerate insight into cardiac signaling networks.
  Journal
Circ Res 108:85-97 (2011)
DOI:10.1161/CIRCRESAHA.110.223602
Reference
  Authors
Schaub MC, Hefti MA, Zaugg M
  Title
Integration of calcium with the signaling network in cardiac myocytes.
  Journal
J Mol Cell Cardiol 41:183-214 (2006)
DOI:10.1016/j.yjmcc.2006.04.005
Reference
  Authors
Taggart P, Boyett MR, Logantha S, Lambiase PD
  Title
Anger, emotion, and arrhythmias: from brain to heart.
  Journal
Front Physiol 2:67 (2011)
DOI:10.3389/fphys.2011.00067
Reference
  Authors
Bers DM
  Title
Calcium cycling and signaling in cardiac myocytes.
  Journal
Annu Rev Physiol 70:23-49 (2008)
DOI:10.1146/annurev.physiol.70.113006.100455
Reference
  Authors
Soltis AR, Saucerman JJ
  Title
Synergy between CaMKII substrates and beta-adrenergic signaling in regulation of cardiac myocyte Ca(2+) handling.
  Journal
Biophys J 99:2038-47 (2010)
DOI:10.1016/j.bpj.2010.08.016
Reference
  Authors
Wallukat G
  Title
The beta-adrenergic receptors.
  Journal
Herz 27:683-90 (2002)
DOI:10.1007/s00059-002-2434-z
Reference
  Authors
Xiao RP
  Title
Beta-adrenergic signaling in the heart: dual coupling of the beta2-adrenergic receptor to G(s) and G(i) proteins.
  Journal
Sci STKE 2001:re15 (2001)
DOI:10.1126/stke.2001.104.re15
Reference
  Authors
Xiao RP, Cheng H, Zhou YY, Kuschel M, Lakatta EG
  Title
Recent advances in cardiac beta(2)-adrenergic signal transduction.
  Journal
Circ Res 85:1092-100 (1999)
DOI:10.1161/01.RES.85.11.1092
Reference
  Authors
Zheng M, Zhu W, Han Q, Xiao RP
  Title
Emerging concepts and therapeutic implications of beta-adrenergic receptor subtype signaling.
  Journal
Pharmacol Ther 108:257-68 (2005)
DOI:10.1016/j.pharmthera.2005.04.006
Reference
  Authors
Kuzumoto M, Takeuchi A, Nakai H, Oka C, Noma A, Matsuoka S
  Title
Simulation analysis of intracellular Na+ and Cl- homeostasis during beta 1-adrenergic stimulation of cardiac myocyte.
  Journal
Prog Biophys Mol Biol 96:171-86 (2008)
DOI:10.1016/j.pbiomolbio.2007.07.005
Reference
  Authors
Bers DM
  Title
Cardiac excitation-contraction coupling.
  Journal
Nature 415:198-205 (2002)
DOI:10.1038/415198a
Reference
  Authors
Ho D, Yan L, Iwatsubo K, Vatner DE, Vatner SF
  Title
Modulation of beta-adrenergic receptor signaling in heart failure and longevity: targeting adenylyl cyclase type 5.
  Journal
Heart Fail Rev 15:495-512 (2010)
DOI:10.1007/s10741-010-9183-5
Reference
  Authors
Saucerman JJ, McCulloch AD
  Title
Mechanistic systems models of cell signaling networks: a case study of myocyte adrenergic regulation.
  Journal
Prog Biophys Mol Biol 85:261-78 (2004)
DOI:10.1016/j.pbiomolbio.2004.01.005
Reference
  Authors
Yano M, Ikeda Y, Matsuzaki M
  Title
Altered intracellular Ca2+ handling in heart failure.
  Journal
J Clin Invest 115:556-64 (2005)
DOI:10.1172/JCI24159
Reference
  Authors
Wehrens XH, Marks AR
  Title
Novel therapeutic approaches for heart failure by normalizing calcium cycling.
  Journal
Nat Rev Drug Discov 3:565-73 (2004)
DOI:10.1038/nrd1440
Reference
  Authors
Triposkiadis F, Karayannis G, Giamouzis G, Skoularigis J, Louridas G, Butler J
  Title
The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications.
  Journal
J Am Coll Cardiol 54:1747-62 (2009)
DOI:10.1016/j.jacc.2009.05.015
Reference
  Authors
Barry SP, Davidson SM, Townsend PA
  Title
Molecular regulation of cardiac hypertrophy.
  Journal
Int J Biochem Cell Biol 40:2023-39 (2008)
DOI:10.1016/j.biocel.2008.02.020

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