KEGG   PATHWAY: apri04261
Entry
apri04261                   Pathway                                
Name
Adrenergic signaling in cardiomyocytes - Ahaetulla prasina (Asian vine snake)
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
apri04261  Adrenergic signaling in cardiomyocytes
apri04261

Other DBs
GO: 0001997
Organism
Ahaetulla prasina (Asian vine snake) [GN:apri]
Gene
131201143  ADRB1; beta-1 adrenergic receptor [KO:K04141]
131193342  ADRB2; beta-2 adrenergic receptor [KO:K04142]
131195588  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoform X1 [KO:K04632]
131198710  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
131195502  ADCY2; adenylate cyclase type 2 isoform X1 [KO:K08042] [EC:4.6.1.1]
131189019  ADCY3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
131197140  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
131204235  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
131191081  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
131184024  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
131195285  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
131184956  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
131194040  BVES; blood vessel epicardial substance [KO:K21108]
131193724  POPDC2; popeye domain-containing protein 2 isoform X1 [KO:K26206]
131194057  POPDC3; popeye domain-containing protein 3 [KO:K26207]
131189300  KCNK2; potassium channel subfamily K member 2 [KO:K04913]
131189981  cAMP-dependent protein kinase catalytic subunit alpha-like [KO:K04345] [EC:2.7.11.11]
131194596  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
131190257  ATP1A1; sodium/potassium-transporting ATPase subunit alpha-1 [KO:K01539] [EC:7.2.2.13]
131186580  sodium/potassium-transporting ATPase subunit alpha-2 [KO:K01539] [EC:7.2.2.13]
131204645  ATP1A3; sodium/potassium-transporting ATPase subunit alpha-3 [KO:K01539] [EC:7.2.2.13]
131188638  sodium/potassium-transporting ATPase subunit alpha-2-like [KO:K01539] [EC:7.2.2.13]
131200636  ATP1B3; sodium/potassium-transporting ATPase subunit beta-3 [KO:K01540]
131197477  ATP1B2; sodium/potassium-transporting ATPase subunit beta-2 [KO:K01540]
131205011  ATP1B4; protein ATP1B4 [KO:K01540]
131204529  SLC9A1; sodium/hydrogen exchanger 1 [KO:K05742]
131202007  potassium voltage-gated channel subfamily KQT member 1-like [KO:K04926]
131185456  KCNQ1; potassium voltage-gated channel subfamily KQT member 1 [KO:K04926]
131199378  KCNE1; potassium voltage-gated channel subfamily E member 1 [KO:K04894]
131200791  plasma membrane calcium-transporting ATPase 1-like [KO:K05850] [EC:7.2.2.10]
131189777  ATP2B2; plasma membrane calcium-transporting ATPase 2 isoform X1 [KO:K05850] [EC:7.2.2.10]
131201934  ATP2B1; plasma membrane calcium-transporting ATPase 1 isoform X1 [KO:K05850] [EC:7.2.2.10]
131192994  ATP2B3; plasma membrane calcium-transporting ATPase 3 isoform X1 [KO:K05850] [EC:7.2.2.10]
131189157  SLC8A1; sodium/calcium exchanger 1 isoform X1 [KO:K05849]
131186411  sodium/calcium exchanger 1-like isoform X1 [KO:K05849]
131204465  SLC8A2; sodium/calcium exchanger 2 isoform X1 [KO:K05849]
131187537  SLC8A3; sodium/calcium exchanger 3 [KO:K05849]
131197664  sodium channel protein type 5 subunit alpha-like [KO:K04838]
131197803  sodium channel protein type 5 subunit alpha-like [KO:K04838]
131198280  LOW QUALITY PROTEIN: sodium channel protein type 5 subunit alpha-like [KO:K04838]
131204781  SCN1B; sodium channel subunit beta-1 [KO:K04845]
131204015  SCN4B; sodium channel subunit beta-4 [KO:K04848]
131202696  CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C [KO:K04850]
131192185  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851]
131191024  CACNA1F; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1F [KO:K04853]
131196419  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S isoform X1 [KO:K04857]
131196633  CACNB1; voltage-dependent L-type calcium channel subunit beta-1 isoform X1 [KO:K04862]
131197764  CACNB2; voltage-dependent L-type calcium channel subunit beta-2 isoform X1 [KO:K04863]
131191462  CACNB3; voltage-dependent L-type calcium channel subunit beta-3 isoform X1 [KO:K04864]
131203006  CACNB4; voltage-dependent L-type calcium channel subunit beta-4 [KO:K04865]
131201691  CACNA2D1; voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X1 [KO:K04858]
131190191  CACNA2D2; voltage-dependent calcium channel subunit alpha-2/delta-2 isoform X1 [KO:K04859]
131191932  CACNA2D3; voltage-dependent calcium channel subunit alpha-2/delta-3 [KO:K04860]
131201975  CACNA2D4; LOW QUALITY PROTEIN: voltage-dependent calcium channel subunit alpha-2/delta-4 [KO:K04861]
131189745  CACNG1; voltage-dependent calcium channel gamma-1 subunit isoform X1 [KO:K04866]
131202648  CACNG2; voltage-dependent calcium channel gamma-2 subunit [KO:K04867]
131185075  CACNG3; voltage-dependent calcium channel gamma-3 subunit [KO:K04868]
131193024  CACNG4; voltage-dependent calcium channel gamma-4 subunit [KO:K04869]
131193256  CACNG5; voltage-dependent calcium channel gamma-5 subunit [KO:K04870]
131196792  CACNG6; voltage-dependent calcium channel gamma-6 subunit [KO:K04871]
131196791  CACNG7; voltage-dependent calcium channel gamma-7 subunit isoform X1 [KO:K04872]
131196796  CACNG8; voltage-dependent calcium channel gamma-8 subunit [KO:K04873]
131189201  CALM2; calmodulin-2 isoform X1 [KO:K02183]
131184677  CALML4; calmodulin-like protein 4 [KO:K02183]
131202068  CALML3; calmodulin-like protein 3 [KO:K02183]
131202069  calmodulin, striated muscle-like [KO:K02183]
131186379  calmodulin-alpha isoform X1 [KO:K02183]
131187145  CALML6; calmodulin-like protein 6 [KO:K02183]
131204579  CALM3; calmodulin-3 [KO:K02183]
131187845  CALM1; calmodulin-1 [KO:K02183]
131200940  CAMK2G; calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X1 [KO:K04515] [EC:2.7.11.17]
131202855  CAMK2D; calcium/calmodulin-dependent protein kinase type II subunit delta isoform X1 [KO:K04515] [EC:2.7.11.17]
131191470  CAMK2A; calcium/calmodulin-dependent protein kinase type II subunit alpha [KO:K04515] [EC:2.7.11.17]
131203754  CAMK2B; calcium/calmodulin-dependent protein kinase type II subunit beta isoform X1 [KO:K04515] [EC:2.7.11.17]
131192290  RYR2; ryanodine receptor 2 [KO:K04962]
131191022  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
131192569  serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform isoform X1 [KO:K04382] [EC:3.1.3.16]
131204438  PPP2R1A; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
131200701  PPP2R2D; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B delta isoform isoform X1 [KO:K04354]
131202956  serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B gamma isoform isoform X1 [KO:K04354]
131203829  PPP2R2A; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform isoform X1 [KO:K04354]
131192118  PPP2R2B; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform isoform X1 [KO:K04354]
131201470  PPP2R3A; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha isoform X1 [KO:K11583]
131187723  PPP2R3C; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma isoform X1 [KO:K11583]
131200185  PPP2R3B; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta isoform X1 [KO:K11583]
131189180  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform isoform X1 [KO:K11584]
131189273  PPP2R5A; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform isoform X1 [KO:K11584]
131186449  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform [KO:K11584]
131187925  PPP2R5C; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X1 [KO:K11584]
131188003  PPP2R5E; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform isoform X1 [KO:K11584]
131185560  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
131187764  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
131192415  TNNC1; troponin C, slow skeletal and cardiac muscles [KO:K05865]
131198085  TNNI3; troponin I, cardiac muscle [KO:K12044]
131195430  TNNT2; troponin T, cardiac muscle isoform X1 [KO:K12045]
131184572  TPM1; tropomyosin alpha-1 chain isoform X1 [KO:K10373]
131192928  TPM2; tropomyosin beta chain isoform X1 [KO:K10374]
131186343  TPM3; tropomyosin alpha-3 chain isoform X1 [KO:K09290]
131188145  TPM4; tropomyosin alpha-4 chain isoform X1 [KO:K10375]
131187318  actin, alpha skeletal muscle B [KO:K12314]
131187687  ACTC1; actin, alpha cardiac muscle 1 [KO:K12314]
131198695  myosin-6-like [KO:K17751]
131198696  myosin-7 [KO:K17751]
131185562  MYL2; myosin regulatory light chain 2, ventricular/cardiac muscle isoform [KO:K10351]
131196751  MYL3; myosin light chain 3 [KO:K12749]
131196634  myosin light chain 4 isoform X1 [KO:K12750]
131193164  PLN; cardiac phospholamban [KO:K05852]
131188825  sarcoplasmic/endoplasmic reticulum calcium ATPase 3 [KO:K05853] [EC:7.2.2.10]
131197095  ATP2A1; sarcoplasmic/endoplasmic reticulum calcium ATPase 1 [KO:K05853] [EC:7.2.2.10]
131185485  ATP2A2; sarcoplasmic/endoplasmic reticulum calcium ATPase 2 isoform X1 [KO:K05853] [EC:7.2.2.10]
131190056  AGT; angiotensinogen [KO:K09821]
131200672  AGTR1; type-1 angiotensin II receptor [KO:K04166]
131205072  AGTR2; type-2 angiotensin II receptor [KO:K04167]
131203954  ADRA1A; alpha-1A adrenergic receptor isoform X1 [KO:K04135]
131203340  ADRA1D; alpha-1D adrenergic receptor [KO:K04137]
131193592  guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
131197358  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
131197364  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
131186410  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
131187650  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
131189703  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
131190607  PPP1R1A; protein phosphatase 1 regulatory subunit 1A [KO:K08050]
131185647  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
131197779  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
131187851  RPS6KA5; ribosomal protein S6 kinase alpha-5 [KO:K04445] [EC:2.7.11.1]
131200000  CREB1; cyclic AMP-responsive element-binding protein 1 [KO:K05870]
131201858  ATF2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
131202229  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
131201832  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
131186340  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
131192921  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
131187455  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
131188389  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
131198637  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
131192474  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
131198985  CREM; cAMP-responsive element modulator isoform X1 [KO:K09052]
131194707  BCL2; apoptosis regulator Bcl-2 [KO:K02161]
131191262  RAPGEF3; rap guanine nucleotide exchange factor 3 [KO:K08014]
131201982  RAPGEF4; rap guanine nucleotide exchange factor 4 [KO:K04351]
131195354  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
131201873  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
131201911  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
131196334  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
131189612  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
131195822  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
131201921  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
131201923  PIK3CG; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform isoform X1 [KO:K21289] [EC:2.7.1.153]
131189775  PIK3R5; phosphoinositide 3-kinase regulatory subunit 5 isoform X1 [KO:K21290]
131189776  PIK3R6; phosphoinositide 3-kinase regulatory subunit 6 isoform X1 [KO:K21290]
131189498  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
131204269  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
131187974  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
apri04020  Calcium signaling pathway
apri04260  Cardiac muscle contraction
KO pathway
ko04261   
LinkDB

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