KEGG   PATHWAY: rno04261
Entry
rno04261                    Pathway                                
Name
Adrenergic signaling in cardiomyocytes - Rattus norvegicus (rat)
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
rno04261  Adrenergic signaling in cardiomyocytes
rno04261

Other DBs
GO: 0001997
Organism
Rattus norvegicus (rat) [GN:rno]
Gene
100362453  Ppp2cal1; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform-like [KO:K04382] [EC:3.1.3.16]
114493  Cacna1f; voltage-dependent L-type calcium channel subunit alpha-1F [KO:K04853]
116590  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
116600  Cacnb2; voltage-dependent L-type calcium channel subunit beta-2 isoform 2 [KO:K04863]
116601  Atp2a1; sarcoplasmic/endoplasmic reticulum calcium ATPase 1 [KO:K05853] [EC:7.2.2.10]
117104  Ppp2r2a; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform [KO:K04354]
117256  Ppp2r2c; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B gamma isoform isoform 1 [KO:K04354]
117281  Ppp2r1a; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform [KO:K03456]
117557  Tpm3; tropomyosin alpha-3 chain isoform Tpm3.3cy [KO:K09290]
140447  Slc8a2; sodium/calcium exchanger 2 precursor [KO:K05849]
140448  Slc8a3; sodium/calcium exchanger 3 precursor [KO:K05849]
140724  Cacng3; voltage-dependent calcium channel gamma-3 subunit [KO:K04868]
140725  Cacng4; voltage-dependent calcium channel gamma-4 subunit [KO:K04869]
140726  Cacng5; voltage-dependent calcium channel gamma-5 subunit [KO:K04870]
140727  Cacng6; voltage-dependent calcium channel gamma-6 subunit [KO:K04871]
140728  Cacng7; voltage-dependent calcium channel gamma-7 subunit [KO:K04872]
140729  Cacng8; voltage-dependent calcium channel gamma-8 subunit [KO:K04873]
170899  Kcnk2; potassium channel subfamily K member 2 isoform 2 [KO:K04913]
171140  Camk2g; calcium/calmodulin-dependent protein kinase type II subunit gamma [KO:K04515] [EC:2.7.11.17]
24173  Adra1b; alpha-1B adrenergic receptor [KO:K04136]
24176  Adrb2; beta-2 adrenergic receptor [KO:K04142]
24179  Agt; angiotensinogen precursor [KO:K09821]
24180  Agtr1a; type-1 angiotensin II receptor A [KO:K04166]
24182  Agtr2; type-2 angiotensin II receptor [KO:K04167]
24185  Akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
24211  Atp1a1; sodium/potassium-transporting ATPase subunit alpha-1 precursor [KO:K01539] [EC:7.2.2.13]
24212  Atp1a2; sodium/potassium-transporting ATPase subunit alpha-2 precursor [KO:K01539] [EC:7.2.2.13]
24213  Atp1a3; sodium/potassium-transporting ATPase subunit alpha-3 [KO:K01539] [EC:7.2.2.13]
24214  Atp1b2; sodium/potassium-transporting ATPase subunit beta-2 [KO:K01540]
24215  Atp2b2; plasma membrane calcium-transporting ATPase 2 [KO:K05850] [EC:7.2.2.10]
24224  Bcl2; apoptosis regulator Bcl-2 [KO:K02161]
24239  Cacna1c; voltage-dependent L-type calcium channel subunit alpha-1C [KO:K04850]
24242  Calm1; calmodulin-1 [KO:K02183]
24244  Calm3; calmodulin-3 [KO:K02183]
24245  Camk2b; calcium/calmodulin-dependent protein kinase type II subunit beta isoform 2 [KO:K04515] [EC:2.7.11.17]
24246  Camk2d; calcium/calmodulin-dependent protein kinase type II subunit delta [KO:K04515] [EC:2.7.11.17]
24585  Myl3; myosin light chain 3 [KO:K12749]
246255  Ppp2r2d; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B delta isoform [KO:K04354]
24654  Plcb1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
24668  Ppp1ca; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
24669  Ppp1cc; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform 1 [KO:K06269] [EC:3.1.3.16]
24672  Ppp2ca; serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform [KO:K04382] [EC:3.1.3.16]
24673  Ppp2cb; serine/threonine-protein phosphatase 2A catalytic subunit beta isoform [KO:K04382] [EC:3.1.3.16]
24680  Prkca; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
24782  Slc9a1; sodium/hydrogen exchanger 1 [KO:K05742]
24837  Tnnt2; troponin T, cardiac muscle isoform 1 [KO:K12045]
24851  Tpm1; tropomyosin alpha-1 chain isoform Tpm1.6cy [KO:K10373]
24852  Tpm4; tropomyosin alpha-4 chain [KO:K10375]
24896  Gnas; SCG6 (secretogranin VI) isoform SCG6 precursor [KO:K04632]
24925  Adrb1; beta-1 adrenergic receptor [KO:K04141]
25031  Plcb4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:3.1.4.11]
25233  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
252857  Rapgef4; rap guanine nucleotide exchange factor 4 [KO:K04351]
25289  Adcy6; adenylate cyclase type 6 isoform 2 [KO:K08046] [EC:4.6.1.1]
25297  Cacnb3; voltage-dependent L-type calcium channel subunit beta-3 [KO:K04864]
25390  Atp1b3; sodium/potassium-transporting ATPase subunit beta-3 [KO:K01540]
25391  Atp2a3; sarcoplasmic/endoplasmic reticulum calcium ATPase 3 [KO:K05853] [EC:7.2.2.10]
25399  Cacna2d1; voltage-dependent calcium channel subunit alpha-2/delta-1 isoform 3 precursor [KO:K04858]
25400  Camk2a; calcium/calmodulin-dependent protein kinase type II subunit alpha [KO:K04515] [EC:2.7.11.17]
25471  Kcne1; potassium voltage-gated channel subfamily E member 1 [KO:K04894]
25594  Ppp1cb; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
25620  Crem; cAMP-responsive element modulator isoform 3 [KO:K09052]
25636  Prkaca; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
25643  Gnai3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
25650  Atp1b1; sodium/potassium-transporting ATPase subunit beta-1 [KO:K01540]
25665  Scn5a; sodium channel protein type 5 subunit alpha isoform 1 [KO:K04838]
25686  Gnai1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
290561  Tnnc1; troponin C, slow skeletal and cardiac muscles [KO:K05865]
29132  Atp1a4; sodium/potassium-transporting ATPase subunit alpha-4 [KO:K01539] [EC:7.2.2.13]
29241  Adcy8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
29248  Tnni3; troponin I, cardiac muscle [KO:K12044]
29275  Actc1; actin, alpha cardiac muscle 1 [KO:K12314]
29322  Plcb3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
293508  Prkacb; cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
29412  Adra1a; alpha-1A adrenergic receptor [KO:K04135]
29413  Adra1d; alpha-1D adrenergic receptor [KO:K04137]
29414  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
29513  Mapk13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
29556  Myh6; myosin-6 [KO:K17751]
29557  Myh7; myosin-7 [KO:K17751]
29598  Atp2b1; plasma membrane calcium-transporting ATPase 1 isoform 3 [KO:K05850] [EC:7.2.2.10]
29599  Atp2b3; plasma membrane calcium-transporting ATPase 3 [KO:K05850] [EC:7.2.2.10]
29600  Atp2b4; plasma membrane calcium-transporting ATPase 4 [KO:K05850] [EC:7.2.2.10]
29639  Fxyd2; sodium/potassium-transporting ATPase subunit gamma isoform a [KO:K01538]
29658  Cacng1; voltage-dependent calcium channel gamma-1 subunit [KO:K04866]
29686  Scn1b; sodium channel subunit beta-1 isoform 1 precursor [KO:K04845]
29693  Atp2a2; sarcoplasmic/endoplasmic reticulum calcium ATPase 2 isoform b [KO:K05853] [EC:7.2.2.10]
29715  Slc8a1; sodium/calcium exchanger 1 isoform 6 precursor [KO:K05849]
29716  Cacna1d; voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851]
298400  Creb3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
298947  Pik3cg; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform [KO:K21289] [EC:2.7.1.153]
299147  Ppp2r5e; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform [KO:K11584]
300992  Cacna2d2; voltage-dependent calcium channel subunit alpha-2/delta-2 precursor [KO:K04859]
302950  Adcy9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
305509  Adcy1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
306243  Cacna2d3; voltage-dependent calcium channel subunit alpha-2/delta-3 precursor [KO:K04860]
307100  Calml3; calmodulin-like protein 3 [KO:K02183]
309179  Ppp2r5b; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform [KO:K11584]
310616  Creb3l4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform 1 [KO:K09048]
312668  Cacna2d4; voltage-dependent calcium channel subunit alpha-2/delta-4 [KO:K04861]
312754  Ppp2r5a; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform [KO:K11584]
314384  Rps6ka5; ribosomal protein S6 kinase alpha-5 [KO:K04445] [EC:2.7.11.1]
314638  Creb3l3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
315611  Scn4b; sodium channel subunit beta-4 precursor [KO:K04848]
315648  Ppp2r1b; serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform [KO:K03456]
360718  Popdc2; popeye domain-containing protein 2 [KO:K26206]
362165  Creb3l1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
362339  Creb3l2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
362739  Ppp2r3c; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma [KO:K11583]
363122  Ppp2r3a; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha [KO:K11583]
363193  Ppp2r5d; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform [KO:K11584]
363925  Myl2; myosin regulatory light chain 2, ventricular/cardiac muscle isoform [KO:K10351]
364774  Calml5; calmodulin-like protein 5 [KO:K02183]
365603  Bves; blood vessel epicardial substance [KO:K21108]
406169  Atf6b; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
497931  Pik3r5; phosphoinositide 3-kinase regulatory subunit 5 [KO:K21290]
497932  Pik3r6; phosphoinositide 3-kinase regulatory subunit 6 [KO:K21290]
500131  Creb5; cyclic AMP-responsive element-binding protein 5 [KO:K09047]
500450  Tpm2; tropomyosin beta chain isoform Tpm2.1sm/cy [KO:K10374]
50663  Calm2; calmodulin-2 [KO:K02183]
50688  Cacnb1; voltage-dependent L-type calcium channel subunit beta-1 [KO:K04862]
50689  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
54223  Adcy4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
58942  Cacnb4; voltage-dependent L-type calcium channel subunit beta-4 isoform 2 [KO:K04865]
58977  Ppp1r1a; protein phosphatase 1 regulatory subunit 1A [KO:K08050]
59326  Rapgef3; rap guanine nucleotide exchange factor 3 [KO:K08014]
60352  Mapk12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
60660  Ppp2r2b; serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform isoform 1 [KO:K04354]
641520  Popdc3; popeye domain-containing protein 3 isoform 2 [KO:K26207]
64155  Scn7a; sodium channel protein type 7 subunit alpha [KO:K04839]
64508  Adcy3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
64532  Adcy5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
64672  Pln; cardiac phospholamban [KO:K05852]
682033  Ppp2r3b; serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta [KO:K11583]
682930  Cacna1s; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
688228  Myl4; myosin light chain 4 [KO:K12750]
689314  Mapk11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
689560  Ryr2; ryanodine receptor 2 isoform 1 [KO:K04962]
691318  Ppp2r5c; serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform isoform 4 [KO:K11584]
691455  Calml4; calmodulin-like protein 4 [KO:K02183]
79255  Atf4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
81636  Adcy2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
81638  Agtr1b; type-1 angiotensin II receptor B [KO:K04166]
81646  Creb1; cyclic AMP-responsive element-binding protein 1 isoform A [KO:K05870]
81647  Atf2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
81649  Mapk14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
81664  Gnai2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
81666  Gnaq; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
84020  Kcnq1; potassium voltage-gated channel subfamily KQT member 1 [KO:K04926]
84347  Cacng2; voltage-dependent calcium channel gamma-2 subunit [KO:K04867]
84396  Atp1b4; protein ATP1B4 [KO:K01540]
84420  Adcy7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
85240  Plcb2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
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
rno04020  Calcium signaling pathway
rno04151  PI3K-Akt signaling pathway
rno04260  Cardiac muscle contraction
KO pathway
ko04261   

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