KEGG   PATHWAY: vvp04261
Entry
vvp04261                    Pathway                                
Name
Adrenergic signaling in cardiomyocytes - Vulpes vulpes (red fox)
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
vvp04261  Adrenergic signaling in cardiomyocytes
vvp04261

Other DBs
GO: 0001997
Organism
Vulpes vulpes (red fox) [GN:vvp]
Gene
112914728  ADRB1; LOW QUALITY PROTEIN: beta-1 adrenergic receptor [KO:K04141]
112927528  ADRB2; beta-2 adrenergic receptor [KO:K04142]
112932168  guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
112932169  neuroendocrine secretory protein 55 [KO:K04632]
112911455  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
112934273  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
112908545  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
112926558  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
112913504  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
112921089  ADCY6; adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
112929565  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
112915982  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
112923266  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
112925136  BVES; blood vessel epicardial substance [KO:K21108]
112913465  POPDC2; LOW QUALITY PROTEIN: popeye domain-containing protein 2 [KO:K26206]
112925137  POPDC3; popeye domain-containing protein 3 [KO:K26207]
112921786  KCNK2; potassium channel subfamily K member 2 isoform X1 [KO:K04913]
112908063  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
112924478  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
112916773  ATP1A1; sodium/potassium-transporting ATPase subunit alpha-1 [KO:K01539] [EC:7.2.2.13]
112931443  ATP1A3; sodium/potassium-transporting ATPase subunit alpha-3 [KO:K01539] [EC:7.2.2.13]
112910077  sodium/potassium-transporting ATPase subunit alpha-2 [KO:K01539] [EC:7.2.2.13]
112910081  sodium/potassium-transporting ATPase subunit alpha-4 [KO:K01539] [EC:7.2.2.13]
112924852  ATP1B2; sodium/potassium-transporting ATPase subunit beta-2 [KO:K01540]
112923490  ATP1B1; sodium/potassium-transporting ATPase subunit beta-1 [KO:K01540]
112934460  ATP1B4; protein ATP1B4 isoform X1 [KO:K01540]
112934973  ATP1B3; sodium/potassium-transporting ATPase subunit beta-3 [KO:K01540]
112920357  FXYD2; sodium/potassium-transporting ATPase subunit gamma isoform X1 [KO:K01538]
112931659  SLC9A1; sodium/hydrogen exchanger 1 [KO:K05742]
112924005  KCNQ1; potassium voltage-gated channel subfamily KQT member 1 [KO:K04926]
112910263  KCNE1; potassium voltage-gated channel subfamily E member 1 [KO:K04894]
112933678  plasma membrane calcium-transporting ATPase 2 [KO:K05850] [EC:7.2.2.10]
112911488  ATP2B3; plasma membrane calcium-transporting ATPase 3 isoform X1 [KO:K05850] [EC:7.2.2.10]
112914901  ATP2B1; plasma membrane calcium-transporting ATPase 1 isoform X1 [KO:K05850] [EC:7.2.2.10]
112914411  ATP2B4; plasma membrane calcium-transporting ATPase 4 isoform X1 [KO:K05850] [EC:7.2.2.10]
112927220  SLC8A3; sodium/calcium exchanger 3 isoform X1 [KO:K05849]
112931343  SLC8A2; sodium/calcium exchanger 2 [KO:K05849]
112935294  SLC8A1; sodium/calcium exchanger 1 isoform X1 [KO:K05849]
112921648  SCN5A; sodium channel protein type 5 subunit alpha isoform X1 [KO:K04838]
112916443  SCN7A; sodium channel protein type 7 subunit alpha [KO:K04839]
112928532  SCN1B; sodium channel subunit beta-1 [KO:K04845]
112920355  SCN4B; sodium channel subunit beta-4 [KO:K04848]
112917426  CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C isoform X1 [KO:K04850]
112910069  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851]
112907237  CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853]
112934538  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
112917793  CACNB1; voltage-dependent L-type calcium channel subunit beta-1 isoform X1 [KO:K04862]
112932853  CACNB2; voltage-dependent L-type calcium channel subunit beta-2 isoform X1 [KO:K04863]
112921092  CACNB3; voltage-dependent L-type calcium channel subunit beta-3 isoform X1 [KO:K04864]
112926879  CACNB4; voltage-dependent L-type calcium channel subunit beta-4 isoform X1 [KO:K04865]
112925398  CACNA2D1; voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X1 [KO:K04858]
112910957  CACNA2D2; voltage-dependent calcium channel subunit alpha-2/delta-2 isoform X1 [KO:K04859]
112909997  CACNA2D3; voltage-dependent calcium channel subunit alpha-2/delta-3 [KO:K04860]
112917422  CACNA2D4; voltage-dependent calcium channel subunit alpha-2/delta-4 [KO:K04861]
112920604  CACNG1; voltage-dependent calcium channel gamma-1 subunit [KO:K04866]
112929089  CACNG2; voltage-dependent calcium channel gamma-2 subunit [KO:K04867]
112908294  CACNG3; voltage-dependent calcium channel gamma-3 subunit [KO:K04868]
112920648  CACNG4; voltage-dependent calcium channel gamma-4 subunit [KO:K04869]
112920727  CACNG5; voltage-dependent calcium channel gamma-5 subunit isoform X1 [KO:K04870]
112909400  CACNG6; voltage-dependent calcium channel gamma-6 subunit isoform X1 [KO:K04871]
112909331  CACNG7; voltage-dependent calcium channel gamma-7 subunit [KO:K04872]
112909396  CACNG8; voltage-dependent calcium channel gamma-8 subunit [KO:K04873]
112927180  calmodulin-alpha-like [KO:K02183]
112926172  CALML6; calmodulin-like protein 6 isoform X1 [KO:K02183]
112915227  CALM2; calmodulin-2 [KO:K02183]
112930936  CALML4; calmodulin-like protein 4 [KO:K02183]
112931188  CALM3; calmodulin-3 [KO:K02183]
112907343  CALM1; calmodulin-1 [KO:K02183]
112907557  CALML5; calmodulin-like protein 5 [KO:K02183]
112933710  CALML3; calmodulin-like protein 3 [KO:K02183]
112931026  CAMK2D; calcium/calmodulin-dependent protein kinase type II subunit delta isoform X1 [KO:K04515] [EC:2.7.11.17]
112924513  CAMK2G; calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X1 [KO:K04515] [EC:2.7.11.17]
112927337  CAMK2A; calcium/calmodulin-dependent protein kinase type II subunit alpha isoform X1 [KO:K04515] [EC:2.7.11.17]
112911701  CAMK2B; calcium/calmodulin-dependent protein kinase type II subunit beta [KO:K04515] [EC:2.7.11.17]
112927407  RYR2; ryanodine receptor 2 [KO:K04962]
112916103  PPP2CB; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
112917055  PPP2CA; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
112925972  PPP2R1B; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X1 [KO:K03456]
112931417  PPP2R1A; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
112926797  PPP2R2A; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform isoform X1 [KO:K04354]
112928797  PPP2R2D; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B delta isoform isoform X1 [KO:K04354]
112920859  PPP2R2C; protein phosphatase 2, regulatory subunit B, gamma isoform X1 [KO:K04354]
112934990  PPP2R2B; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform isoform X1 [KO:K04354]
112908961  PPP2R3B; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta isoform X1 [KO:K11583]
112932510  PPP2R3A; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha [KO:K11583]
112935323  PPP2R3C; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma isoform X1 [KO:K11583]
112930274  PPP2R5C; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X1 [KO:K11584]
112924290  PPP2R5B; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform isoform X1 [KO:K11584]
112921765  PPP2R5A; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
112913999  PPP2R5D; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
112921351  PPP2R5E; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform isoform X1 [KO:K11584]
112933024  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
112924187  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
112935190  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
112910492  TNNC1; troponin C, slow skeletal and cardiac muscles isoform X1 [KO:K05865]
112909344  TNNI3; troponin I, cardiac muscle [KO:K12044]
112934536  TNNT2; troponin T, cardiac muscle isoform X1 [KO:K12045]
112922859  TPM1; tropomyosin alpha-1 chain isoform X1 [KO:K10373]
112930822  TPM2; tropomyosin beta chain isoform X1 [KO:K10374]
112914127  tropomyosin-like [KO:K10374]
112913093  tropomyosin alpha-3 chain-like [KO:K09290]
112918879  TPM3; tropomyosin alpha-3 chain isoform X1 [KO:K09290]
112913137  TPM4; tropomyosin alpha-4 chain isoform X1 [KO:K10375]
112920713  tropomyosin alpha-4 chain [KO:K10375]
112919920  ACTC1; actin, alpha cardiac muscle 1 [KO:K12314]
112926472  myosin-7 [KO:K17751]
112926516  myosin-6 [KO:K17751]
112935243  MYL2; myosin regulatory light chain 2, ventricular/cardiac muscle isoform [KO:K10351]
112913253  MYL3; myosin light chain 3 [KO:K12749]
112920591  MYL4; myosin light chain 4 [KO:K12750]
112922761  PLN; cardiac phospholamban [KO:K05852]
112935193  ATP2A2; sarcoplasmic/endoplasmic reticulum calcium ATPase 2 [KO:K05853] [EC:7.2.2.10]
112911398  ATP2A3; sarcoplasmic/endoplasmic reticulum calcium ATPase 3 isoform X1 [KO:K05853] [EC:7.2.2.10]
112929189  ATP2A1; sarcoplasmic/endoplasmic reticulum calcium ATPase 1 isoform X1 [KO:K05853] [EC:7.2.2.10]
112927331  AGT; angiotensinogen [KO:K09821]
112932806  AGTR1; type-1 angiotensin II receptor [KO:K04166]
112910724  AGTR2; type-2 angiotensin II receptor [KO:K04167]
112926793  ADRA1A; alpha-1A adrenergic receptor isoform X1 [KO:K04135]
112928138  ADRA1B; alpha-1B adrenergic receptor [KO:K04136]
112930031  ADRA1D; LOW QUALITY PROTEIN: alpha-1D adrenergic receptor [KO:K04137]
112922087  guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
112924037  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
112930053  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
112930054  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
112919942  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
112920728  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
112911291  PPP1R1A; protein phosphatase 1 regulatory subunit 1A isoform X1 [KO:K08050]
112929340  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
112907501  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
112907322  RPS6KA5; ribosomal protein S6 kinase alpha-5 isoform X1 [KO:K04445] [EC:2.7.11.1]
112922611  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
112916383  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
112934037  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
112930843  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
112918871  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
112924095  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
112935546  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
112908881  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
112915694  cyclic AMP-responsive element-binding protein 5 [KO:K09047]
112913633  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
112921560  CREM; cAMP-responsive element modulator isoform X1 [KO:K09052]
112919203  BCL2; apoptosis regulator Bcl-2 [KO:K02161]
112921075  RAPGEF3; rap guanine nucleotide exchange factor 3 isoform X1 [KO:K08014]
112916400  RAPGEF4; rap guanine nucleotide exchange factor 4 isoform X1 [KO:K04351]
112913931  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
112913932  MAPK13; mitogen-activated protein kinase 13 isoform X1 [KO:K04441] [EC:2.7.11.24]
112935862  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
112935863  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
112911158  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 isoform X1 [KO:K04630]
112918267  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
112925393  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 isoform X1 [KO:K04630]
112908560  PIK3CG; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform [KO:K21289] [EC:2.7.1.153]
112924887  PIK3R6; phosphoinositide 3-kinase regulatory subunit 6 [KO:K21290]
112924888  PIK3R5; phosphoinositide 3-kinase regulatory subunit 5 isoform X1 [KO:K21290]
112928376  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
112930303  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
112923528  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [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
vvp04020  Calcium signaling pathway
vvp04151  PI3K-Akt signaling pathway
vvp04260  Cardiac muscle contraction
KO pathway
ko04261   
LinkDB

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