Pathway Map Details

Development_Beta-adrenergic receptors signaling via cAMP

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BETA-PIX, Ca('2+) = Ca('2+), AMP, PKA-reg type II (cAMP-dependent), Ca('2+) endoplasmic reticulum lumen, cAMP, Calcineurin A (beta), Troponin cardiac, PPAR-gamma, LIPS, CaMK II, MEKK4(MAP3K4), PKA-cat (cAMP-dependent), PYGM, Ryanodine receptor 2, Ca('2) cytosol, PPARGC1 (PGC1-alpha), Beta-3 adrenergic receptor, PP2A catalytic, Perilipin, Ca-ATPase1, Adrenaline extracellular region, Phospholamban, UCP1, ATP, PRKAR2A, PDE3A, Beta-1 adrenergic receptor, Beta-2 adrenergic receptor, L-type Ca(II) channel, alpha 1C subunit, Adenylate cyclase, CDC42,, ATP + H(,2)O + Ca('2+) = ADP + phosphate + Ca('2+), Noradrenaline extracellular region, PKA-reg type II (cAMP-dependent)(human), PHK alpha (muscle), PPAR-gamma/RXR-alpha, Troponin I, cardiac, PHK gamma (muscle), Ca('2+) = Ca('2+), p38 MAPK, AKAP6, PDE4D, MEK3(MAP2K3), Ca('2+) extracellular region, Ca-ATPase2, Calmodulin, G-protein alpha-s, MEK6(MAP2K6), Troponin C, cardiac,


Beta-adrenergic receptors signaling via cAMP

Beta-1, Beta-2 and Beta-3 adrenergic receptors are activated by Adrenaline and Noradrenaline. Conventional signaling is accomplished via GNAS complex locus ( G-protein alpha-s )/ Adenylate cyclase that leads to Adenosine 3',5'-cyclic phosphate ( cAMP ) production and activation of Protein kinase cAMP-dependent regulatory and catalytic ( PKA-reg (cAMP-dependent) and PKA-cat (cAMP-dependent) ) [1]. A kinase anchor protein 6 ( AKAP6 ) is an anchor protein that enables PKA-cat phosphorylation [2], [3]. Beta-2 adrenergic receptor signaling appears to be localized to plasma membrane, unlike that of Beta-1 adrenergic receptor [4].

Beta-1 adrenergic receptor coupled PKA-cat phosphorylates Phospholamban. Phosphorylation of Phospholamban is believed to release its tonic inhibition of ATPase Ca++ transporting cardiac muscle fast twitch 1 and slow twitch 2 ( Ca-ATPase1 and Ca-ATPase2 ) and to Ca('2) cytosol flux to endoplasmatic reticulum. Ca('2) flux from cytoplasm accelerates relaxation of cardiomyocytes [5].

Also PKA-cat phosphorylates Troponin I type 3 ( Troponin I, cardiac ) . Phosphorylation prevents Troponin I interaction with Troponin C type 1 ( Troponin C, cardiac ) and leads to weaker Ca('2) binding and thereby to relaxation of cardiac myocytes. [6], [5]. PKA-cat -mediated phosphorylation of Troponin I is antagonized by dephosphorylation by Protein phosphatase 2 catalytic subunit ( PP2A catalytic ) [7].

PKA-cat phosphorylation of Ryanodine receptor 2 leads to elevated Ca('2+) flux to cytoplasm. Elevated Ca('2+) in cardiac muscles normally has chronotropic effect [3], [5]

PKA-cat, e.g., in cardiomyocytes, activates Phosphorylase kinase alpha 1 and gamma 1 ( PHK alpha (muscle) and PHK gamma (muscle) )/ Phosphorylase glycogen muscle ( PYGM ) and this leads to acceleration of glycogen breakdown rate [6], [5].

Activated by Beta-1 and Beta-2 adrenergic receptors, PKA-cat participates in activation of Calcium channel voltage-dependent L type alpha 1C subunit ( L-type Ca(II) channel, alpha 1C subunit). Ca('2) current via L-type Ca(II) channels elevates Ca('2) levels in cytosol. This process leads to contraction of cardiomyocytes [4], [8]. Elevated level of Ca('2) in cardiomyocytes leads to activation of ( Calmodulin )/ ( CaMK II ). CaMK II phospholylates L-type Ca(II) channel and Phospholamban [5]. PKA-cat -mediated activation of Phosphodiesterases 4D cAMP-specific ( PDE4D ) and 3A cGMP-inhibited ( PDE3A ) leads to decrease in cAMP level in cytoplasm due to conversion of cAMP to AMP by PDE [9], [10], [5].

PKA-cat activated by Beta-2 and Beta-3 adrenergic receptors presumably phosphorylates Rho guanine nucleotide exchange factor 7 ( BETA-PIX ) [11] which in turn activates Cell division cycle 42 ( CDC42 )/ Mitogen-activated protein kinase kinase kinase ( 4MEKK4(MAP3K4) )/ Mitogen-activated protein kinase kinase 6 and 3 ( MEK6(MAP2K6) and MEK3(MAP2K3) )/ Mitogen-activated protein kinase 14 ( p38 MAPK ) [12], [13], leading to relaxation of cariomyocytes [12]. In white/brown adipocytes and intestinal smooth muscle cells, the above ivents lead to activation of Peroxisome proliferator-activated receptor gamma coactivator 1 alpha ( PPARGC1 (PGC1-alpha) )/ Peroxisome proliferator-activated receptor gamma ( PPAR-gamma ). PPAR-gamma is in a complex with Retinoid X receptor alpha ( PPAR-gamma/RXR-alpha ) that participates in transcriptional activation of Uncoupling protein 1 ( UCP1 ). UCP1 participates in physiological processes of nonshivering thermogenesis in brown adipocites and in relaxation of intestinal smooth muscle cells [13], [14].

PKA-cat activated by Beta-3 adrenergic receptor phosphorylates Lipase hormone-sensitive ( LIPS ) and Perilipin, the latter being a facilitator of LIPS activity. This way, Beta-3 adrenergic receptor stimulates lipolysis [15].


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    Structure and function of beta3-adrenergic receptors. Medicina (Kaunas, Lithuania) 2004;40(5):407-13
  2. Fink MA, Zakhary DR, Mackey JA, Desnoyer RW, Apperson-Hansen C, Damron DS, Bond M
    AKAP-mediated targeting of protein kinase a regulates contractility in cardiac myocytes. Circulation research 2001 Feb 16;88(3):291-7
  3. Pare GC, Bauman AL, McHenry M, Michel JJ, Dodge-Kafka KL, Kapiloff MS
    The mAKAP complex participates in the induction of cardiac myocyte hypertrophy by adrenergic receptor signaling. Journal of cell science 2005 Dec 1;118(Pt 23):5637-46
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    beta2-adrenergic cAMP signaling is uncoupled from phosphorylation of cytoplasmic proteins in canine heart. Circulation 1999 May 11;99(18):2458-65
  7. Deshmukh PA, Blunt BC, Hofmann PA
    Acute modulation of PP2a and troponin I phosphorylation in ventricular myocytes: studies with a novel PP2a peptide inhibitor. American journal of physiology. Heart and circulatory physiology 2007 Feb;292(2):H792-9
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    G(i)-dependent localization of beta(2)-adrenergic receptor signaling to L-type Ca(2+) channels. Biophysical journal 2000 Nov;79(5):2547-56
  9. Rochais F, Vandecasteele G, Lefebvre F, Lugnier C, Lum H, Mazet JL, Cooper DM, Fischmeister R
    Negative feedback exerted by cAMP-dependent protein kinase and cAMP phosphodiesterase on subsarcolemmal cAMP signals in intact cardiac myocytes: an in vivo study using adenovirus-mediated expression of CNG channels. The Journal of biological chemistry 2004 Dec 10;279(50):52095-105
  10. Ding B, Abe J, Wei H, Huang Q, Walsh RA, Molina CA, Zhao A, Sadoshima J, Blaxall BC, Berk BC, Yan C
    Functional role of phosphodiesterase 3 in cardiomyocyte apoptosis: implication in heart failure. Circulation 2005 May 17;111(19):2469-76
  11. Lee SH, Eom M, Lee SJ, Kim S, Park HJ, Park D
    BetaPix-enhanced p38 activation by Cdc42/Rac/PAK/MKK3/6-mediated pathway. Implication in the regulation of membrane ruffling. The Journal of biological chemistry 2001 Jul 6;276(27):25066-72
  12. Zheng M, Zhang SJ, Zhu WZ, Ziman B, Kobilka BK, Xiao RP
    beta 2-adrenergic receptor-induced p38 MAPK activation is mediated by protein kinase A rather than by Gi or gbeta gamma in adult mouse cardiomyocytes. The Journal of biological chemistry 2000 Dec 22;275(51):40635-40
  13. Cao W, Medvedev AV, Daniel KW, Collins S
    beta-Adrenergic activation of p38 MAP kinase in adipocytes: cAMP induction of the uncoupling protein 1 (UCP1) gene requires p38 MAP kinase. The Journal of biological chemistry 2001 Jul 20;276(29):27077-82
  14. Shabalina I, Wiklund C, Bengtsson T, Jacobsson A, Cannon B, Nedergaard J
    Uncoupling protein-1: involvement in a novel pathway for beta-adrenergic, cAMP-mediated intestinal relaxation. American journal of physiology. Gastrointestinal and liver physiology 2002 Nov;283(5):G1107-16
  15. Robidoux J, Kumar N, Daniel KW, Moukdar F, Cyr M, Medvedev AV, Collins S
    Maximal beta3-adrenergic regulation of lipolysis involves Src and epidermal growth factor receptor-dependent ERK1/2 activation. The Journal of biological chemistry 2006 Dec 8;281(49):37794-802