KEGG   PATHWAY: ncar04261
Entry
ncar04261                   Pathway                                
Name
Adrenergic signaling in cardiomyocytes - Sciurus carolinensis (gray squirrel)
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
ncar04261  Adrenergic signaling in cardiomyocytes
ncar04261

Other DBs
GO: 0001997
Organism
Sciurus carolinensis (gray squirrel) [GN:ncar]
Gene
124985454  beta-1 adrenergic receptor [KO:K04141]
124987131  beta-2 adrenergic receptor [KO:K04142]
124978161  neuroendocrine secretory protein 55 [KO:K04632]
124975134  guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
124990345  adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
124987010  adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
124962927  adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
124978229  LOW QUALITY PROTEIN: adenylate cyclase type 4-like [KO:K08044] [EC:4.6.1.1]
124992559  adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:4.6.1.1]
124983776  adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
124966834  adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
124965096  adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
124970113  LOW QUALITY PROTEIN: adenylate cyclase type 9-like [KO:K08049] [EC:4.6.1.1]
124989656  blood vessel epicardial substance isoform X1 [KO:K21108]
124993027  popeye domain-containing protein 2 isoform X1 [KO:K26206]
124988663  popeye domain-containing protein 3 [KO:K26207]
124961818  potassium channel subfamily K member 2 isoform X1 [KO:K04913]
124985819  cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
124969119  cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
124967385  sodium/potassium-transporting ATPase subunit alpha-3 isoform X1 [KO:K01539] [EC:7.2.2.13]
124979517  sodium/potassium-transporting ATPase subunit alpha-2 [KO:K01539] [EC:7.2.2.13]
124981180  LOW QUALITY PROTEIN: sodium/potassium-transporting ATPase subunit alpha-1-like [KO:K01539] [EC:7.2.2.13]
124992537  sodium/potassium-transporting ATPase subunit beta-3 isoform X1 [KO:K01540]
124961571  sodium/potassium-transporting ATPase subunit beta-1 [KO:K01540]
124981128  sodium/potassium-transporting ATPase subunit beta-2 [KO:K01540]
124972490  protein ATP1B4 isoform X1 [KO:K01540]
124960527  sodium/potassium-transporting ATPase subunit gamma-like isoform X1 [KO:K01538]
124990681  sodium/hydrogen exchanger 1 [KO:K05742]
124960101  potassium voltage-gated channel subfamily KQT member 1 isoform X1 [KO:K04926]
124993042  potassium voltage-gated channel subfamily E member 1-like [KO:K04894]
124962398  plasma membrane calcium-transporting ATPase 4 isoform X1 [KO:K05850] [EC:7.2.2.10]
124970941  plasma membrane calcium-transporting ATPase 2 isoform X1 [KO:K05850] [EC:7.2.2.10]
124971750  plasma membrane calcium-transporting ATPase 3 isoform X1 [KO:K05850] [EC:7.2.2.10]
124983674  plasma membrane calcium-transporting ATPase 1 isoform X1 [KO:K05850] [EC:7.2.2.10]
124977782  sodium/calcium exchanger 3 isoform X1 [KO:K05849]
124963285  sodium/calcium exchanger 1 isoform X1 [KO:K05849]
124966297  sodium/calcium exchanger 2 isoform X1 [KO:K05849]
124968422  sodium channel protein type 5 subunit alpha isoform X1 [KO:K04838]
124980680  LOW QUALITY PROTEIN: sodium channel protein type 7 subunit alpha-like [KO:K04839]
124966413  sodium channel subunit beta-1 isoform X1 [KO:K04845]
124960557  sodium channel subunit beta-4 isoform X1 [KO:K04848]
124982084  voltage-dependent L-type calcium channel subunit alpha-1C [KO:K04850]
124968359  LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1D-like [KO:K04851]
124971751  voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853]
124961645  voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
124980591  voltage-dependent L-type calcium channel subunit beta-1 isoform X1 [KO:K04862]
124961976  LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit beta-2-like [KO:K04863]
124982456  LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit beta-3-like [KO:K04864]
124979835  voltage-dependent L-type calcium channel subunit beta-4 isoform X1 [KO:K04865]
124990321  voltage-dependent calcium channel subunit alpha-2/delta-1 isoform X1 [KO:K04858]
124992864  voltage-dependent calcium channel subunit alpha-2/delta-2 isoform X1 [KO:K04859]
124969140  voltage-dependent calcium channel subunit alpha-2/delta-3 isoform X1 [KO:K04860]
124982731  voltage-dependent calcium channel subunit alpha-2/delta-4 [KO:K04861]
124980463  voltage-dependent calcium channel gamma-1 subunit [KO:K04866]
124982217  voltage-dependent calcium channel gamma-2 subunit isoform X1 [KO:K04867]
124970546  voltage-dependent calcium channel gamma-3 subunit [KO:K04868]
124981165  voltage-dependent calcium channel gamma-4 subunit [KO:K04869]
124980471  voltage-dependent calcium channel gamma-5 subunit [KO:K04870]
124966274  voltage-dependent calcium channel gamma-6 subunit [KO:K04871]
124966037  voltage-dependent calcium channel gamma-7 subunit isoform X1 [KO:K04872]
124967101  voltage-dependent calcium channel gamma-8 subunit [KO:K04873]
124976834  LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
124967357  calmodulin-1 [KO:K02183]
124967948  calmodulin-like protein 6 [KO:K02183]
124962006  calmodulin-like [KO:K02183]
124962112  calmodulin-A-like [KO:K02183]
124962222  calmodulin-like protein 3 [KO:K02183]
124963056  calmodulin-1 [KO:K02183]
124976085  calmodulin-1 [KO:K02183]
124985817  calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X1 [KO:K04515] [EC:2.7.11.17]
124986742  calcium/calmodulin-dependent protein kinase type II subunit alpha isoform X1 [KO:K04515] [EC:2.7.11.17]
124994412  calcium/calmodulin-dependent protein kinase type II subunit delta isoform X1 [KO:K04515] [EC:2.7.11.17]
124990768  calcium/calmodulin-dependent protein kinase type II subunit beta isoform X1 [KO:K04515] [EC:2.7.11.17]
124961919  ryanodine receptor 2 isoform X1 [KO:K04962]
124987135  serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
124983945  serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
124958287  serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform isoform X1 [KO:K03456]
124967003  serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
124986762  serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform isoform X1 [KO:K04354]
124994837  serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B gamma isoform isoform X1 [KO:K04354]
124984746  serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B delta isoform isoform X1 [KO:K04354]
124982397  serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform isoform X1 [KO:K04354]
124993238  serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha isoform X1 [KO:K11583]
124977718  serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma isoform X1 [KO:K11583]
124962449  serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma-like [KO:K11583]
124975681  serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta isoform X1 [KO:K11583]
124958310  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform [KO:K11584]
124988657  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform isoform X1 [KO:K11584]
124976854  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform X1 [KO:K11584]
124961576  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
124973978  LOW QUALITY PROTEIN: serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform-like [KO:K11584]
124976126  serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform isoform X1 [KO:K11584]
124991738  serine/threonine-protein phosphatase PP1-gamma catalytic subunit [KO:K06269] [EC:3.1.3.16]
124960013  serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
124963007  serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
124969118  troponin C, slow skeletal and cardiac muscles [KO:K05865]
124966930  troponin I, cardiac muscle isoform X1 [KO:K12044]
124961491  troponin T, cardiac muscle isoform X1 [KO:K12045]
124964713  tropomyosin beta chain isoform X1 [KO:K10374]
124993462  tropomyosin alpha-3 chain isoform X1 [KO:K09290]
124974851  LOW QUALITY PROTEIN: tropomyosin alpha-3 chain-like [KO:K09290]
124983652  tropomyosin alpha-3 chain-like isoform X1 [KO:K09290]
124968391  tropomyosin alpha-1 chain isoform X1 [KO:K10375]
124971702  actin, alpha cardiac muscle 1 [KO:K12314]
124977759  myosin-6 [KO:K17751]
124977760  myosin-7 [KO:K17751]
124990741  myosin regulatory light chain 2, ventricular/cardiac muscle isoform isoform X1 [KO:K10351]
124969421  myosin light chain 3 [KO:K12749]
124980434  myosin light chain 4 [KO:K12750]
124988557  cardiac phospholamban [KO:K05852]
124990126  sarcoplasmic/endoplasmic reticulum calcium ATPase 2 [KO:K05853] [EC:7.2.2.10]
124969905  sarcoplasmic/endoplasmic reticulum calcium ATPase 1 [KO:K05853] [EC:7.2.2.10]
124980515  sarcoplasmic/endoplasmic reticulum calcium ATPase 3 isoform X1 [KO:K05853] [EC:7.2.2.10]
124961133  angiotensinogen-like [KO:K09821]
124992863  type-1 angiotensin II receptor [KO:K04166]
124972584  type-2 angiotensin II receptor [KO:K04167]
124982077  alpha-1A adrenergic receptor isoform X1 [KO:K04135]
124987385  alpha-1B adrenergic receptor [KO:K04136]
124972007  alpha-1D adrenergic receptor [KO:K04137]
124964255  guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
124976705  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
124959812  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
124977474  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
124972679  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
124979014  protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
124983447  protein phosphatase 1 regulatory subunit 1A isoform X1 [KO:K08050]
124990635  LOW QUALITY PROTEIN: mitogen-activated protein kinase 1-like [KO:K04371] [EC:2.7.11.24]
124970294  mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
124977339  ribosomal protein S6 kinase alpha-5 isoform X1 [KO:K04445] [EC:2.7.11.1]
124979032  cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
124979831  LOW QUALITY PROTEIN: cyclic AMP-dependent transcription factor ATF-2-like [KO:K04450]
124984025  cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
124991113  cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
124958938  cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048]
124984689  cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
124969564  cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
124964377  cyclic AMP-responsive element-binding protein 3-like isoform X1 [KO:K09048]
124991182  cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
124988573  cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
124962339  cAMP-responsive element modulator isoform X1 [KO:K09052]
124965545  apoptosis regulator Bcl-2 [KO:K02161]
124982354  rap guanine nucleotide exchange factor 3 isoform X1 [KO:K08014]
124978987  rap guanine nucleotide exchange factor 4 isoform X1 [KO:K04351]
124988515  mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
124989076  mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
124978202  mitogen-activated protein kinase 14-like isoform X1 [KO:K04441] [EC:2.7.11.24]
124982485  mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
124982486  LOW QUALITY PROTEIN: mitogen-activated protein kinase 11-like [KO:K04441] [EC:2.7.11.24]
124992673  guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
124988012  guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
124991078  guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
124991973  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform isoform X1 [KO:K21289] [EC:2.7.1.153]
124980224  phosphoinositide 3-kinase regulatory subunit 6 isoform X1 [KO:K21290]
124981277  phosphoinositide 3-kinase regulatory subunit 5 isoform X1 [KO:K21290]
124962260  LOW QUALITY PROTEIN: RAC-gamma serine/threonine-protein kinase-like [KO:K04456] [EC:2.7.11.1]
124976076  RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
124966582  RAC-beta 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
ncar04020  Calcium signaling pathway
ncar04151  PI3K-Akt signaling pathway
ncar04260  Cardiac muscle contraction
KO pathway
ko04261   
LinkDB

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