KEGG   PATHWAY: lav04261
Entry
lav04261                    Pathway                                
Name
Adrenergic signaling in cardiomyocytes - Loxodonta africana (African savanna elephant)
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
lav04261  Adrenergic signaling in cardiomyocytes
lav04261

Other DBs
GO: 0001997
Organism
Loxodonta africana (African savanna elephant) [GN:lav]
Gene
100654973  ADRB1; LOW QUALITY PROTEIN: beta-1 adrenergic receptor [KO:K04141]
100664615  ADRB2; beta-2 adrenergic receptor [KO:K04142]
100655206  guanine nucleotide-binding protein G(s) subunit alpha isoform X1 [KO:K04632]
100669226  neuroendocrine secretory protein 55-like [KO:K04632]
100671072  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
100673570  ADCY2; LOW QUALITY PROTEIN: adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
100674724  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
100675525  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
100670244  ADCY5; LOW QUALITY PROTEIN: adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
100653532  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
100653771  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
100661616  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
100663448  ADCY9; LOW QUALITY PROTEIN: adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
100669239  BVES; blood vessel epicardial substance [KO:K21108]
100660296  POPDC2; popeye domain-containing protein 2 [KO:K26206]
100661393  POPDC3; popeye domain-containing protein 3 [KO:K26207]
100654542  KCNK2; potassium channel subfamily K member 2 isoform X1 [KO:K04913]
100656966  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
100674245  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
100668326  ATP1A3; LOW QUALITY PROTEIN: sodium/potassium-transporting ATPase subunit alpha-3 [KO:K01539] [EC:7.2.2.13]
100667801  sodium/potassium-transporting ATPase subunit alpha-4 [KO:K01539] [EC:7.2.2.13]
100674070  ATP1A2; sodium/potassium-transporting ATPase subunit alpha-2 [KO:K01539] [EC:7.2.2.13]
100661428  ATP1A1; sodium/potassium-transporting ATPase subunit alpha-1 [KO:K01539] [EC:7.2.2.13]
100655666  ATP1B3; sodium/potassium-transporting ATPase subunit beta-3 [KO:K01540]
100660792  ATP1B4; protein ATP1B4 isoform X2 [KO:K01540]
100676526  ATP1B1; sodium/potassium-transporting ATPase subunit beta-1 [KO:K01540]
100668753  ATP1B2; sodium/potassium-transporting ATPase subunit beta-2 [KO:K01540]
111752838  FXYD2; sodium/potassium-transporting ATPase subunit gamma [KO:K01538]
104846349  SLC9A1; sodium/hydrogen exchanger 1 [KO:K05742]
100666129  KCNQ1; LOW QUALITY PROTEIN: potassium voltage-gated channel subfamily KQT member 1 [KO:K04926]
100666451  KCNE1; potassium voltage-gated channel subfamily E member 1 [KO:K04894]
100656297  ATP2B4; plasma membrane calcium-transporting ATPase 4 isoform X1 [KO:K05850] [EC:7.2.2.10]
100656553  ATP2B1; plasma membrane calcium-transporting ATPase 1 isoform X1 [KO:K05850] [EC:7.2.2.10]
100656362  ATP2B3; plasma membrane calcium-transporting ATPase 3 [KO:K05850] [EC:7.2.2.10]
100655542  ATP2B2; plasma membrane calcium-transporting ATPase 2 [KO:K05850] [EC:7.2.2.10]
100666349  SLC8A3; sodium/calcium exchanger 3 [KO:K05849]
100658790  SLC8A1; sodium/calcium exchanger 1 isoform X2 [KO:K05849]
100661888  SLC8A2; sodium/calcium exchanger 2 [KO:K05849]
100672206  SCN7A; sodium channel protein type 7 subunit alpha [KO:K04839]
100674190  SCN1B; LOW QUALITY PROTEIN: sodium channel subunit beta-1 [KO:K04845]
100658893  SCN4B; sodium channel subunit beta-4 isoform X2 [KO:K04848]
100659992  CACNA1D; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851]
100674649  CACNA1F; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1F [KO:K04853]
100673089  CACNA1S; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
104846285  CACNB1; voltage-dependent L-type calcium channel subunit beta-1 isoform X1 [KO:K04862]
100673091  CACNB2; voltage-dependent L-type calcium channel subunit beta-2 [KO:K04863]
100653996  CACNB3; voltage-dependent L-type calcium channel subunit beta-3 isoform X4 [KO:K04864]
100656938  CACNB4; voltage-dependent L-type calcium channel subunit beta-4 [KO:K04865]
100676022  CACNA2D1; voltage-dependent calcium channel subunit alpha-2/delta-1 [KO:K04858]
100667110  CACNA2D2; voltage-dependent calcium channel subunit alpha-2/delta-2 [KO:K04859]
100659138  CACNA2D3; LOW QUALITY PROTEIN: voltage-dependent calcium channel subunit alpha-2/delta-3 [KO:K04860]
100663604  CACNA2D4; voltage-dependent calcium channel subunit alpha-2/delta-4 [KO:K04861]
100666105  CACNG1; voltage-dependent calcium channel gamma-1 subunit [KO:K04866]
100672366  CACNG3; voltage-dependent calcium channel gamma-3 subunit [KO:K04868]
100664775  CACNG4; voltage-dependent calcium channel gamma-4 subunit [KO:K04869]
100665821  CACNG5; voltage-dependent calcium channel gamma-5 subunit isoform X2 [KO:K04870]
111749631  CACNG6; voltage-dependent calcium channel gamma-6 subunit [KO:K04871]
100672020  CACNG7; voltage-dependent calcium channel gamma-7 subunit [KO:K04872]
100660460  CACNG8; voltage-dependent calcium channel gamma-8 subunit [KO:K04873]
100663507  CALM1; calmodulin-1 [KO:K02183]
100664679  CALM2; calmodulin-2 [KO:K02183]
100657612  calmodulin [KO:K02183]
100669885  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
100658962  CALML3; calmodulin-like protein 3 [KO:K02183]
100658208  calmodulin [KO:K02183]
104846071  CAMK2A; calcium/calmodulin-dependent protein kinase type II subunit alpha [KO:K04515] [EC:2.7.11.17]
100653927  CAMK2G; calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X1 [KO:K04515] [EC:2.7.11.17]
100663321  CAMK2D; calcium/calmodulin-dependent protein kinase type II subunit delta isoform X2 [KO:K04515] [EC:2.7.11.17]
100658516  CAMK2B; calcium/calmodulin-dependent protein kinase type II subunit beta [KO:K04515] [EC:2.7.11.17]
100676989  ryanodine receptor 2 [KO:K04962]
100664132  PPP2CA; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
100676230  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
100654486  PPP2R1A; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
100663532  PPP2R1B; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X1 [KO:K03456]
100666680  PPP2R2D; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B delta isoform isoform X2 [KO:K04354]
100668825  PPP2R2A; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform isoform X2 [KO:K04354]
100666413  PPP2R2B; LOW QUALITY PROTEIN: serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform [KO:K04354]
100668487  PPP2R3A; LOW QUALITY PROTEIN: serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha [KO:K11583]
100663566  serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta [KO:K11583]
100670795  PPP2R3C; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma isoform X1 [KO:K11583]
100659955  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
100675562  PPP2R5E; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform isoform X1 [KO:K11584]
100676500  PPP2R5C; LOW QUALITY PROTEIN: serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform [KO:K11584]
100660424  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform [KO:K11584]
100659875  PPP2R5A; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
100660199  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
100673814  PPP1CA; LOW QUALITY PROTEIN: serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
100671604  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
100660968  TNNC1; troponin C, slow skeletal and cardiac muscles isoform X1 [KO:K05865]
100670991  TNNT2; troponin T, cardiac muscle [KO:K12045]
100666675  TPM1; tropomyosin alpha-1 chain isoform X5 [KO:K10373]
100653632  TPM2; tropomyosin beta chain isoform X3 [KO:K10374]
100674827  TPM3; tropomyosin alpha-3 chain isoform X1 [KO:K09290]
100671189  TPM4; tropomyosin alpha-4 chain [KO:K10375]
100658146  ACTC1; actin, alpha cardiac muscle 1 [KO:K12314]
100670087  myosin-6 isoform X1 [KO:K17751]
100670377  LOW QUALITY PROTEIN: myosin-7 [KO:K17751]
100656780  MYL3; myosin light chain 3 [KO:K12749]
100665527  MYL4; myosin light chain 4 [KO:K12750]
100665933  PLN; cardiac phospholamban [KO:K05852]
100676453  ATP2A1; sarcoplasmic/endoplasmic reticulum calcium ATPase 1 isoform X2 [KO:K05853] [EC:7.2.2.10]
100671775  ATP2A3; sarcoplasmic/endoplasmic reticulum calcium ATPase 3 isoform X6 [KO:K05853] [EC:7.2.2.10]
100670753  ATP2A2; sarcoplasmic/endoplasmic reticulum calcium ATPase 2 [KO:K05853] [EC:7.2.2.10]
100670141  AGT; LOW QUALITY PROTEIN: angiotensinogen [KO:K09821]
100659079  AGTR1; type-1 angiotensin II receptor [KO:K04166]
100666379  AGTR2; type-2 angiotensin II receptor [KO:K04167]
100668259  ADRA1A; alpha-1A adrenergic receptor [KO:K04135]
100675999  ADRA1B; alpha-1B adrenergic receptor [KO:K04136]
100656672  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha isoform X1 [KO:K04634]
100670617  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X3 [KO:K05858] [EC:3.1.4.11]
100672435  PLCB1; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
100668575  PLCB2; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
100663829  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
100665537  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
100665944  PPP1R1A; protein phosphatase 1 regulatory subunit 1A [KO:K08050]
100658240  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100665157  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100664075  RPS6KA5; ribosomal protein S6 kinase alpha-5 isoform X1 [KO:K04445] [EC:2.7.11.1]
100675162  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
100657989  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
100662521  ATF4; cyclic AMP-dependent transcription factor ATF-4 isoform X2 [KO:K04374]
100653565  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
100673694  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
100666211  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
100670574  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
100677344  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
100675079  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
100666885  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X2 [KO:K09049]
100661010  CREM; cAMP-responsive element modulator isoform X14 [KO:K09052]
100675268  BCL2; apoptosis regulator Bcl-2 [KO:K02161]
100655802  RAPGEF3; LOW QUALITY PROTEIN: rap guanine nucleotide exchange factor 3 [KO:K08014]
100660747  RAPGEF4; rap guanine nucleotide exchange factor 4 [KO:K04351]
100673331  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
100656926  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
100661039  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
100666344  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
100670234  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
100667957  GNAI3; LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
100673566  PIK3CG; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform [KO:K21289] [EC:2.7.1.153]
100670067  PIK3R5; phosphoinositide 3-kinase regulatory subunit 5 isoform X1 [KO:K21290]
100674744  PIK3R6; phosphoinositide 3-kinase regulatory subunit 6 isoform X1 [KO:K21290]
100663184  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100657536  AKT3; RAC-gamma serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
100660187  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
lav04020  Calcium signaling pathway
lav04151  PI3K-Akt signaling pathway
lav04260  Cardiac muscle contraction
KO pathway
ko04261   
LinkDB

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