KEGG   PATHWAY: ko04261
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
Pathway map
ko04261  Adrenergic signaling in cardiomyocytes
ko04261

Other DBs
GO: 0001997
Orthology
K01538  FXYD2, ATP1G1; sodium/potassium-transporting ATPase subunit gamma (FXYD domain-containing ion transport regulator 2)
K01539  ATP1A; sodium/potassium-transporting ATPase subunit alpha [EC:7.2.2.13]
K01540  ATP1B, CD298; sodium/potassium-transporting ATPase subunit beta
K02161  BCL2; apoptosis regulator Bcl-2
K02183  CALM; calmodulin
K02677  PRKCA; classical protein kinase C alpha type [EC:2.7.11.13]
K03456  PPP2R1; serine/threonine-protein phosphatase 2A regulatory subunit A
K04135  ADRA1A; adrenergic receptor alpha-1A
K04136  ADRA1B; adrenergic receptor alpha-1B
K04137  ADRA1D; adrenergic receptor alpha-1D
K04141  ADRB1; adrenergic receptor beta-1
K04142  ADRB2; adrenergic receptor beta-2
K04166  AGTR1; angiotensin II receptor type 1
K04167  AGTR2; angiotensin II receptor type 2
K04345  PKA; protein kinase A [EC:2.7.11.11]
K04351  RAPGEF4, EPAC2; Rap guanine nucleotide exchange factor 4
K04354  PPP2R2; serine/threonine-protein phosphatase 2A regulatory subunit B
K04371  ERK, MAPK1_3; mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K04374  ATF4, CREB2; cyclic AMP-dependent transcription factor ATF-4
K04382  PPP2C; serine/threonine-protein phosphatase 2A catalytic subunit [EC:3.1.3.16]
K04441  P38; p38 MAP kinase [EC:2.7.11.24]
K04445  RPS6KA5, MSK1; ribosomal protein S6 kinase alpha-5 [EC:2.7.11.1]
K04450  ATF2, CREBP1; cyclic AMP-dependent transcription factor ATF-2
K04456  AKT; RAC serine/threonine-protein kinase [EC:2.7.11.1]
K04515  CAMK2; calcium/calmodulin-dependent protein kinase (CaM kinase) II [EC:2.7.11.17]
K04630  GNAI; guanine nucleotide-binding protein G(i) subunit alpha
K04632  GNAS; guanine nucleotide-binding protein G(s) subunit alpha
K04634  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha
K04838  SCN5A, NAV1.5; voltage-gated sodium channel type V alpha
K04839  SCN7A, SCN6A; voltage-gated sodium channel type VII alpha
K04845  SCN1B; voltage-gated sodium channel type I beta
K04848  SCN4B; voltage-gated sodium channel type IV beta
K04850  CACNA1C, CAV1.2; voltage-dependent calcium channel L type alpha-1C
K04851  CACNA1D, CAV1.3; voltage-dependent calcium channel L type alpha-1D
K04853  CACNA1F, CAV1.4; voltage-dependent calcium channel L type alpha-1F
K04857  CACNA1S, CAV1.1; voltage-dependent calcium channel L type alpha-1S
K04858  CACNA2D1; voltage-dependent calcium channel alpha-2/delta-1
K04859  CACNA2D2; voltage-dependent calcium channel alpha-2/delta-2
K04860  CACNA2D3; voltage-dependent calcium channel alpha-2/delta-3
K04861  CACNA2D4; voltage-dependent calcium channel alpha-2/delta-4
K04862  CACNB1; voltage-dependent calcium channel beta-1
K04863  CACNB2; voltage-dependent calcium channel beta-2
K04864  CACNB3; voltage-dependent calcium channel beta-3
K04865  CACNB4; voltage-dependent calcium channel beta-4
K04866  CACNG1; voltage-dependent calcium channel gamma-1
K04867  CACNG2; voltage-dependent calcium channel gamma-2
K04868  CACNG3; voltage-dependent calcium channel gamma-3
K04869  CACNG4; voltage-dependent calcium channel gamma-4
K04870  CACNG5; voltage-dependent calcium channel gamma-5
K04871  CACNG6; voltage-dependent calcium channel gamma-6
K04872  CACNG7; voltage-dependent calcium channel gamma-7
K04873  CACNG8; voltage-dependent calcium channel gamma-8
K04894  KCNE1; potassium voltage-gated channel Isk-related subfamily E member 1
K04913  KCNK2, K2P2.1; potassium channel subfamily K member 2
K04926  KCNQ1, KV7.1; potassium voltage-gated channel KQT-like subfamily member 1
K04962  RYR2; ryanodine receptor 2
K05742  SLC9A1, NHE1; solute carrier family 9 (sodium/hydrogen exchanger), member 1
K05849  SLC8A, NCX; solute carrier family 8 (sodium/calcium exchanger)
K05850  ATP2B; P-type Ca2+ transporter type 2B [EC:7.2.2.10]
K05852  PLN; phospholamban
K05853  ATP2A; P-type Ca2+ transporter type 2A [EC:7.2.2.10]
K05858  PLCB; phosphatidylinositol phospholipase C, beta [EC:3.1.4.11]
K05865  TNNC1; troponin C, slow skeletal and cardiac muscles
K05870  CREB1; cyclic AMP-responsive element-binding protein 1
K06269  PPP1C; serine/threonine-protein phosphatase PP1 catalytic subunit [EC:3.1.3.16]
K08014  RAPGEF3, EPAC1; Rap guanine nucleotide exchange factor 3
K08041  ADCY1; adenylate cyclase 1 [EC:4.6.1.1]
K08042  ADCY2; adenylate cyclase 2 [EC:4.6.1.1]
K08043  ADCY3; adenylate cyclase 3 [EC:4.6.1.1]
K08044  ADCY4; adenylate cyclase 4 [EC:4.6.1.1]
K08045  ADCY5; adenylate cyclase 5 [EC:4.6.1.1]
K08046  ADCY6; adenylate cyclase 6 [EC:4.6.1.1]
K08047  ADCY7; adenylate cyclase 7 [EC:4.6.1.1]
K08048  ADCY8; adenylate cyclase 8 [EC:4.6.1.1]
K08049  ADCY9; adenylate cyclase 9 [EC:4.6.1.1]
K08050  PPP1R1A; protein phosphatase 1 regulatory subunit 1A
K09047  CREB5, CREBPA; cyclic AMP-responsive element-binding protein 5
K09048  CREB3; cyclic AMP-responsive element-binding protein 3
K09049  ATF6B, CREBL1; cyclic AMP-dependent transcription factor ATF-6 beta
K09052  CREM; cAMP response element modulator
K09290  TPM3; tropomyosin 3
K09821  AGT, SERPINA8; angiotensinogen
K10351  MYL2; myosin regulatory light chain 2
K10373  TPM1; tropomyosin 1
K10374  TPM2; tropomyosin 2
K10375  TPM4; tropomyosin 4
K11583  PPP2R3; serine/threonine-protein phosphatase 2A regulatory subunit B''
K11584  PPP2R5; serine/threonine-protein phosphatase 2A regulatory subunit B'
K12044  TNNI3; troponin I, cardiac muscle
K12045  TNNT2; troponin T, cardiac muscle
K12314  ACTC1; actin, alpha cardiac muscle
K12749  MYL3; myosin light chain 3
K12750  MYL4; myosin light chain 4
K17751  MYH6_7; myosin heavy chain 6/7
K21108  BVES, POPDC1; blood vessel epicardial substance
K21289  PIK3CG; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma [EC:2.7.1.153]
K21290  PIK3R5_6; phosphoinositide-3-kinase regulatory subunit 5/6
K26206  POPDC2; popeye domain-containing protein 2
K26207  POPDC3; popeye domain-containing protein 3
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
PMID:19883653
  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
PMID:21212391
  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
PMID:16765984
  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
PMID:22022314
  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
PMID:17988210
  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
PMID:20923637
  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
PMID:12439640
  Authors
Wallukat G
  Title
The beta-adrenergic receptors.
  Journal
Herz 27:683-90 (2002)
DOI:10.1007/s00059-002-2434-z
Reference
PMID:11604549
  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
PMID:10571541
  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
PMID:15979723
  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
PMID:17826821
  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
PMID:11805843
  Authors
Bers DM
  Title
Cardiac excitation-contraction coupling.
  Journal
Nature 415:198-205 (2002)
DOI:10.1038/415198a
Reference
PMID:20658186
  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
PMID:15142747
  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
PMID:15765137
  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
PMID:15232578
  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
PMID:19874988
  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
PMID:18407781
  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
Related
pathway
ko04020  Calcium signaling pathway
ko04151  PI3K-Akt signaling pathway
ko04260  Cardiac muscle contraction

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