KEGG   PATHWAY: dle04261
Entry
dle04261                    Pathway                                
Name
Adrenergic signaling in cardiomyocytes - Delphinapterus leucas (beluga whale)
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
dle04261  Adrenergic signaling in cardiomyocytes
dle04261

Other DBs
GO: 0001997
Organism
Delphinapterus leucas (beluga whale) [GN:dle]
Gene
111163022  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
111163304  SLC9A1; sodium/hydrogen exchanger 1 [KO:K05742]
111163607  ATP2B1; plasma membrane calcium-transporting ATPase 1 isoform X1 [KO:K05850] [EC:7.2.2.10]
111163846  KCNE1; potassium voltage-gated channel subfamily E member 1 [KO:K04894]
111163908  RYR2; ryanodine receptor 2 isoform X1 [KO:K04962]
111163985  AGT; angiotensinogen [KO:K09821]
111164053  POPDC3; popeye domain-containing protein 3 [KO:K26207]
111164225  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
111164400  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
111164599  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
111164603  PIK3CG; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform isoform X1 [KO:K21289] [EC:2.7.1.153]
111164625  CACNA2D1; voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X1 [KO:K04858]
111164991  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
111165040  PLN; cardiac phospholamban [KO:K05852]
111165617  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
111165653  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
111166195  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
111166330  CACNB1; voltage-dependent L-type calcium channel subunit beta-1 isoform X1 [KO:K04862]
111166617  TPM4; tropomyosin alpha-4 chain isoform X1 [KO:K10375]
111166674  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
111166879  SCN4B; sodium channel subunit beta-4 isoform X1 [KO:K04848]
111166927  FXYD2; sodium/potassium-transporting ATPase subunit gamma isoform X1 [KO:K01538]
111166986  [KO:K01539] [EC:7.2.2.13]
111166987  [KO:K01539] [EC:7.2.2.13]
111167157  TPM3; tropomyosin alpha-3 chain isoform X1 [KO:K09290]
111167181  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
111167389  ATP1B1; sodium/potassium-transporting ATPase subunit beta-1 [KO:K01540]
111167657  POPDC2; popeye domain-containing protein 2 isoform X1 [KO:K26206]
111168062  PPP2R1B; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform [KO:K03456]
111168235  ATP1B4; protein ATP1B4 isoform X1 [KO:K01540]
111168265  PPP2R3B; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta isoform X1 [KO:K11583]
111168318  TNNT2; troponin T, cardiac muscle isoform X1 [KO:K12045]
111168340  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
111168810  BVES; blood vessel epicardial substance [KO:K21108]
111168980  ATP2B2; plasma membrane calcium-transporting ATPase 2 isoform X1 [KO:K05850] [EC:7.2.2.10]
111169060  AGTR2; type-2 angiotensin II receptor [KO:K04167]
111169457  SCN5A; sodium channel protein type 5 subunit alpha [KO:K04838]
111169490  CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853]
111170127  [KO:K02183]
111170588  ATP2B3; plasma membrane calcium-transporting ATPase 3 isoform X1 [KO:K05850] [EC:7.2.2.10]
111170633  ADRA1B; alpha-1B adrenergic receptor [KO:K04136]
111170946  ATF6B; LOW QUALITY PROTEIN: cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
111171650  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
111171769  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
111172180  PPP2R2D; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B delta isoform isoform X1 [KO:K04354]
111172295  ADRB1; beta-1 adrenergic receptor [KO:K04141]
111172760  CACNB4; voltage-dependent L-type calcium channel subunit beta-4 isoform X1 [KO:K04865]
111172822  SCN7A; sodium channel protein type 7 subunit alpha [KO:K04839]
111172871  RAPGEF4; rap guanine nucleotide exchange factor 4 isoform X1 [KO:K04351]
111172890  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
111173015  SLC8A3; sodium/calcium exchanger 3 [KO:K05849]
111173081  PPP2R5E; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform isoform X1 [KO:K11584]
111173231  PPP2R3C; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma isoform X1 [KO:K11583]
111173481  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
111173912  PPP1R1A; protein phosphatase 1 regulatory subunit 1A isoform X1 [KO:K08050]
111174035  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
111174049  CACNB3; voltage-dependent L-type calcium channel subunit beta-3 isoform X1 [KO:K04864]
111174075  RAPGEF3; rap guanine nucleotide exchange factor 3 isoform X3 [KO:K08014]
111174141  TNNC1; troponin C, slow skeletal and cardiac muscles isoform X1 [KO:K05865]
111174274  CACNA2D3; voltage-dependent calcium channel subunit alpha-2/delta-3 isoform X2 [KO:K04860]
111174277  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851]
111174353  CACNA2D2; voltage-dependent calcium channel subunit alpha-2/delta-2 isoform X1 [KO:K04859]
111174368  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
111174466  MYL3; myosin light chain 3 [KO:K12749]
111174571  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
111174776  [KO:K09290]
111174794  CALM2; calmodulin-2 [KO:K02183]
111174840  SLC8A1; sodium/calcium exchanger 1 isoform X1 [KO:K05849]
111174925  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
111175000  ADCY3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
111176008  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
111176064  PPP2R5C; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X1 [KO:K11584]
111176157  RPS6KA5; ribosomal protein S6 kinase alpha-5 isoform X1 [KO:K04445] [EC:2.7.11.1]
111176162  CALM1; calmodulin-1 [KO:K02183]
111176547  CACNA2D4; voltage-dependent calcium channel subunit alpha-2/delta-4 [KO:K04861]
111176594  CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C [KO:K04850]
111177559  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
111177687  TPM1; tropomyosin alpha-1 chain isoform X1 [KO:K10373]
111177758  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
111177962  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
111178030  CREM; cAMP-responsive element modulator isoform X1 [KO:K09052]
111178115  CACNB2; voltage-dependent L-type calcium channel subunit beta-2 isoform X1 [KO:K04863]
111178380  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
111178556  ADCY2; adenylate cyclase type 2 isoform X1 [KO:K08042] [EC:4.6.1.1]
111178736  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
111178738  MAPK13; mitogen-activated protein kinase 13 isoform X2 [KO:K04441] [EC:2.7.11.24]
111178838  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
111179116  PPP2R2C; protein phosphatase 2, regulatory subunit B, gamma isoform X1 [KO:K04354]
111179211  PPP2R3A; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha isoform X1 [KO:K11583]
111179257  ATP1B3; sodium/potassium-transporting ATPase subunit beta-3 [KO:K01540]
111179290  AGTR1; type-1 angiotensin II receptor [KO:K04166]
111179983  ATP1A1; sodium/potassium-transporting ATPase subunit alpha-1 [KO:K01539] [EC:7.2.2.13]
111180070  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha [KO:K04630]
111180199  BCL2; apoptosis regulator Bcl-2 [KO:K02161]
111180225  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
111180685  SLC8A2; sodium/calcium exchanger 2 [KO:K05849]
111180711  CALM3; calmodulin-3 [KO:K02183]
111180802  ATP1A3; sodium/potassium-transporting ATPase subunit alpha-3 isoform X1 [KO:K01539] [EC:7.2.2.13]
111180855  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
111180996  CACNG8; voltage-dependent calcium channel gamma-8 subunit [KO:K04873]
111181016  CACNG7; voltage-dependent calcium channel gamma-7 subunit [KO:K04872]
111181019  CACNG6; voltage-dependent calcium channel gamma-6 subunit isoform X1 [KO:K04871]
111181027  TNNI3; troponin I, cardiac muscle isoform X1 [KO:K12044]
111181079  PPP2R1A; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform isoform X1 [KO:K03456]
111181202  SCN1B; sodium channel subunit beta-1 isoform X1 [KO:K04845]
111181753  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
111181781  ACTC1; actin, alpha cardiac muscle 1 [KO:K12314]
111182181  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
111182199  ATP2A1; sarcoplasmic/endoplasmic reticulum calcium ATPase 1 isoform X1 [KO:K05853] [EC:7.2.2.10]
111182231  CACNG3; voltage-dependent calcium channel gamma-3 subunit isoform X1 [KO:K04868]
111182447  PPP2CA; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
111182587  MYL4; myosin light chain 4 isoform X1 [KO:K12750]
111182917  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
111182918  CACNG5; voltage-dependent calcium channel gamma-5 subunit isoform X1 [KO:K04870]
111182919  CACNG4; voltage-dependent calcium channel gamma-4 subunit isoform X1 [KO:K04869]
111182970  CACNG1; voltage-dependent calcium channel gamma-1 subunit [KO:K04866]
111183056  PPP2R2B; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform isoform X1 [KO:K04354]
111183067  ADRB2; beta-2 adrenergic receptor isoform X1 [KO:K04142]
111183091  CAMK2A; calcium/calmodulin-dependent protein kinase type II subunit alpha isoform X1 [KO:K04515] [EC:2.7.11.17]
111183530  CAMK2G; calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X1 [KO:K04515] [EC:2.7.11.17]
111183613  KCNQ1; potassium voltage-gated channel subfamily KQT member 1 isoform X1 [KO:K04926]
111183676  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
111183787  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform isoform X1 [KO:K11584]
111183812  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
111183987  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
111184409  ADRA1D; alpha-1D adrenergic receptor isoform X1 [KO:K04137]
111184516  CAMK2B; calcium/calmodulin-dependent protein kinase type II subunit beta isoform X1 [KO:K04515] [EC:2.7.11.17]
111184534  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
111184609  KCNK2; potassium channel subfamily K member 2 [KO:K04913]
111184699  PPP2R5A; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
111184798  ATP2B4; plasma membrane calcium-transporting ATPase 4 isoform X1 [KO:K05850] [EC:7.2.2.10]
111185250  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
111185411  ADRA1A; alpha-1A adrenergic receptor isoform X1 [KO:K04135]
111185417  PPP2R2A; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform isoform X1 [KO:K04354]
111185833  ATP1B2; sodium/potassium-transporting ATPase subunit beta-2 isoform X1 [KO:K01540]
111185895  ATP2A3; sarcoplasmic/endoplasmic reticulum calcium ATPase 3 isoform X1 [KO:K05853] [EC:7.2.2.10]
111186004  PIK3R5; phosphoinositide 3-kinase regulatory subunit 5 isoform X1 [KO:K21290]
111186025  PIK3R6; phosphoinositide 3-kinase regulatory subunit 6 isoform X1 [KO:K21290]
111186068  CAMK2D; calcium/calmodulin-dependent protein kinase type II subunit delta isoform X1 [KO:K04515] [EC:2.7.11.17]
111186212  ATF4; cyclic AMP-dependent transcription factor ATF-4 isoform X1 [KO:K04374]
111186361  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
111186364  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
111186741  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
111186746  [KO:K04632]
111186906  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
111186914  ATP2A2; sarcoplasmic/endoplasmic reticulum calcium ATPase 2 [KO:K05853] [EC:7.2.2.10]
111187002  MYL2; myosin regulatory light chain 2, ventricular/cardiac muscle isoform [KO:K10351]
111187200  CALML6; calmodulin-like protein 6 [KO:K02183]
111187803  CACNG2; voltage-dependent calcium channel gamma-2 subunit [KO:K04867]
111188007  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
111188045  TPM2; tropomyosin beta chain isoform X1 [KO:K10374]
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
dle04020  Calcium signaling pathway
dle04151  PI3K-Akt signaling pathway
dle04260  Cardiac muscle contraction
KO pathway
ko04261   

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