KEGG   PATHWAY: ray04261
Entry
ray04261                    Pathway                                
Name
Adrenergic signaling in cardiomyocytes - Rousettus aegyptiacus (Egyptian rousette)
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
ray04261  Adrenergic signaling in cardiomyocytes
ray04261

Other DBs
GO: 0001997
Organism
Rousettus aegyptiacus (Egyptian rousette) [GN:ray]
Gene
107511714  ADRB1; beta-1 adrenergic receptor [KO:K04141]
107513544  ADRB2; beta-2 adrenergic receptor [KO:K04142]
107500068  neuroendocrine secretory protein 55-like [KO:K04632]
107500067  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoform X1 [KO:K04632]
107512406  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
107502700  ADCY2; LOW QUALITY PROTEIN: adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
107498506  ADCY3; LOW QUALITY PROTEIN: adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
107498014  ADCY4; LOW QUALITY PROTEIN: adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
107518038  ADCY5; LOW QUALITY PROTEIN: adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
107514224  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
107512248  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
107497689  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
107521680  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
107500710  BVES; blood vessel epicardial substance [KO:K21108]
107508369  POPDC2; popeye domain-containing protein 2 isoform X1 [KO:K26206]
107500711  POPDC3; popeye domain-containing protein 3 [KO:K26207]
107521645  KCNK2; potassium channel subfamily K member 2 isoform X1 [KO:K04913]
107519437  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
107511590  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
107499819  ATP1A1; sodium/potassium-transporting ATPase subunit alpha-1 isoform X1 [KO:K01539] [EC:7.2.2.13]
107502600  ATP1A3; sodium/potassium-transporting ATPase subunit alpha-3 [KO:K01539] [EC:7.2.2.13]
107507949  ATP1A2; sodium/potassium-transporting ATPase subunit alpha-2 isoform X1 [KO:K01539] [EC:7.2.2.13]
107507966  ATP1A4; sodium/potassium-transporting ATPase subunit alpha-4 [KO:K01539] [EC:7.2.2.13]
107509410  ATP1B3; LOW QUALITY PROTEIN: sodium/potassium-transporting ATPase subunit beta-3 [KO:K01540]
107512755  ATP1B1; sodium/potassium-transporting ATPase subunit beta-1 [KO:K01540]
107515690  ATP1B2; sodium/potassium-transporting ATPase subunit beta-2 [KO:K01540]
107498709  ATP1B4; protein ATP1B4 isoform X1 [KO:K01540]
107505043  FXYD2; sodium/potassium-transporting ATPase subunit gamma isoform X1 [KO:K01538]
107503560  SLC9A1; sodium/hydrogen exchanger 1 [KO:K05742]
107503177  KCNQ1; LOW QUALITY PROTEIN: potassium voltage-gated channel subfamily KQT member 1 [KO:K04926]
107520362  potassium voltage-gated channel subfamily E member 1-like [KO:K04894]
107504061  ATP2B3; plasma membrane calcium-transporting ATPase 3 isoform X1 [KO:K05850] [EC:7.2.2.10]
107508151  ATP2B4; LOW QUALITY PROTEIN: plasma membrane calcium-transporting ATPase 4 [KO:K05850] [EC:7.2.2.10]
107520906  ATP2B1; plasma membrane calcium-transporting ATPase 1 isoform X1 [KO:K05850] [EC:7.2.2.10]
107498349  ATP2B2; plasma membrane calcium-transporting ATPase 2 isoform X1 [KO:K05850] [EC:7.2.2.10]
107503262  SLC8A3; sodium/calcium exchanger 3 isoform X1 [KO:K05849]
107516018  SLC8A2; sodium/calcium exchanger 2 isoform X1 [KO:K05849]
107509443  SLC8A1; sodium/calcium exchanger 1 isoform X1 [KO:K05849]
107499591  SCN5A; sodium channel protein type 5 subunit alpha [KO:K04838]
107521052  SCN7A; LOW QUALITY PROTEIN: sodium channel protein type 7 subunit alpha [KO:K04839]
107504253  SCN1B; sodium channel subunit beta-1 [KO:K04845]
107516119  SCN4B; sodium channel subunit beta-4 [KO:K04848]
107500540  CACNA1C; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1C [KO:K04850]
107516535  CACNA1D; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851]
107514999  CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853]
107513628  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
107520701  CACNB1; voltage-dependent L-type calcium channel subunit beta-1 isoform X1 [KO:K04862]
107513663  CACNB2; voltage-dependent L-type calcium channel subunit beta-2 isoform X1 [KO:K04863]
107514227  CACNB3; voltage-dependent L-type calcium channel subunit beta-3 isoform X1 [KO:K04864]
107513916  CACNB4; voltage-dependent L-type calcium channel subunit beta-4 isoform X1 [KO:K04865]
107501281  CACNA2D1; voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X1 [KO:K04858]
107513293  CACNA2D2; LOW QUALITY PROTEIN: voltage-dependent calcium channel subunit alpha-2/delta-2 [KO:K04859]
107516533  CACNA2D3; LOW QUALITY PROTEIN: voltage-dependent calcium channel subunit alpha-2/delta-3 [KO:K04860]
107500543  CACNA2D4; voltage-dependent calcium channel subunit alpha-2/delta-4 [KO:K04861]
107510248  CACNG1; voltage-dependent calcium channel gamma-1 subunit [KO:K04866]
107519239  CACNG2; voltage-dependent calcium channel gamma-2 subunit [KO:K04867]
107508836  CACNG3; voltage-dependent calcium channel gamma-3 subunit [KO:K04868]
107510310  CACNG4; voltage-dependent calcium channel gamma-4 subunit [KO:K04869]
107510308  CACNG5; voltage-dependent calcium channel gamma-5 subunit [KO:K04870]
107503034  CACNG6; voltage-dependent calcium channel gamma-6 subunit [KO:K04871]
107503063  CACNG7; voltage-dependent calcium channel gamma-7 subunit [KO:K04872]
107503036  CACNG8; LOW QUALITY PROTEIN: voltage-dependent calcium channel gamma-8 subunit [KO:K04873]
107509556  CALM2; calmodulin [KO:K02183]
107508927  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
107515457  CALM1; calmodulin [KO:K02183]
107516034  CALM3; calmodulin [KO:K02183]
107501627  calmodulin-like protein 5 [KO:K02183]
107510894  CAMK2D; calcium/calmodulin-dependent protein kinase type II subunit delta isoform X1 [KO:K04515] [EC:2.7.11.17]
107512385  CAMK2B; calcium/calmodulin-dependent protein kinase type II subunit beta isoform X1 [KO:K04515] [EC:2.7.11.17]
107497167  CAMK2A; calcium/calmodulin-dependent protein kinase type II subunit alpha isoform X1 [KO:K04515] [EC:2.7.11.17]
107498266  CAMK2G; calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X1 [KO:K04515] [EC:2.7.11.17]
107520024  RYR2; LOW QUALITY PROTEIN: ryanodine receptor 2 [KO:K04962]
107506800  PPP2CA; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
107505807  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
107521184  PPP2R1B; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X1 [KO:K03456]
107500417  PPP2R1A; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
107519027  PPP2R2C; protein phosphatase 2, regulatory subunit B, gamma isoform X1 [KO:K04354]
107515450  PPP2R2A; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform isoform X1 [KO:K04354]
107500870  PPP2R2B; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform isoform X1 [KO:K04354]
107514412  PPP2R3C; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma isoform X1 [KO:K11583]
107505863  PPP2R3B; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta isoform X1 [KO:K11583]
107508495  PPP2R3A; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha isoform X1 [KO:K11583]
107509328  PPP2R5E; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform isoform X1 [KO:K11584]
107517041  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform isoform X1 [KO:K11584]
107521366  PPP2R5C; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X1 [KO:K11584]
107521621  PPP2R5A; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
107501966  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
107511165  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
107503728  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
107513247  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
107498574  TNNC1; troponin C, slow skeletal and cardiac muscles [KO:K05865]
107515439  TNNI3; troponin I, cardiac muscle [KO:K12044]
107513651  TNNT2; troponin T, cardiac muscle isoform X1 [KO:K12045]
107508997  TPM1; tropomyosin alpha-1 chain isoform X1 [KO:K10373]
107502868  TPM2; tropomyosin beta chain isoform X1 [KO:K10374]
107509189  TPM3; tropomyosin alpha-3 chain isoform X1 [KO:K09290]
107517241  TPM4; tropomyosin alpha-4 chain isoform X1 [KO:K10375]
107508080  ACTC1; actin, alpha cardiac muscle 1 [KO:K12314]
107498010  MYH6; myosin-6 [KO:K17751]
107498011  myosin-7 [KO:K17751]
107513248  MYL2; myosin regulatory light chain 2, ventricular/cardiac muscle isoform [KO:K10351]
107509109  MYL3; myosin light chain 3 [KO:K12749]
107508180  MYL4; myosin light chain 4 isoform X1 [KO:K12750]
107515126  PLN; cardiac phospholamban [KO:K05852]
107515804  ATP2A1; sarcoplasmic/endoplasmic reticulum calcium ATPase 1 isoform X1 [KO:K05853] [EC:7.2.2.10]
107507669  ATP2A3; sarcoplasmic/endoplasmic reticulum calcium ATPase 3 isoform X1 [KO:K05853] [EC:7.2.2.10]
107513235  ATP2A2; sarcoplasmic/endoplasmic reticulum calcium ATPase 2 [KO:K05853] [EC:7.2.2.10]
107520073  AGT; LOW QUALITY PROTEIN: angiotensinogen [KO:K09821]
107513418  AGTR1; type-1 angiotensin II receptor [KO:K04166]
107517857  AGTR2; type-2 angiotensin II receptor [KO:K04167]
107515454  ADRA1A; alpha-1A adrenergic receptor isoform X1 [KO:K04135]
107521889  ADRA1B; alpha-1B adrenergic receptor [KO:K04136]
107505691  ADRA1D; LOW QUALITY PROTEIN: alpha-1D adrenergic receptor [KO:K04137]
107517194  GNAQ; LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
107506114  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
107519930  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
107497081  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
107514464  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
107510307  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
107521072  PPP1R1A; protein phosphatase 1 regulatory subunit 1A isoform X1 [KO:K08050]
107515836  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
107497830  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
107515442  RPS6KA5; ribosomal protein S6 kinase alpha-5 isoform X1 [KO:K04445] [EC:2.7.11.1]
107505169  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
107504977  ATF2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
107500816  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
107509179  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
107502779  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
107511864  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
107510647  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
107499057  CREB3L2; LOW QUALITY PROTEIN: cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
107505683  CREB5; cyclic AMP-responsive element-binding protein 5 [KO:K09047]
107498439  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
107520743  CREM; cAMP-responsive element modulator isoform X1 [KO:K09052]
107503915  BCL2; apoptosis regulator Bcl-2 isoform X1 [KO:K02161]
107499884  RAPGEF3; rap guanine nucleotide exchange factor 3 isoform X1 [KO:K08014]
107505164  RAPGEF4; rap guanine nucleotide exchange factor 4 isoform X1 [KO:K04351]
107497883  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
107497895  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
107500264  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
107500274  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
107516134  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
107518173  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
107513376  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
107511488  PIK3CG; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform isoform X1 [KO:K21289] [EC:2.7.1.153]
107515658  PIK3R5; phosphoinositide 3-kinase regulatory subunit 5 isoform X1 [KO:K21290]
107515659  PIK3R6; phosphoinositide 3-kinase regulatory subunit 6 isoform X1 [KO:K21290]
107513978  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
107521783  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
107498395  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [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
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
ray04020  Calcium signaling pathway
ray04151  PI3K-Akt signaling pathway
ray04260  Cardiac muscle contraction
KO pathway
ko04261   
LinkDB

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