Development - Beta-adrenergic receptors signaling via cAMP

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Beta-adrenergic receptors signaling via cAMP

Beta-1 adrenergic receptor, Beta-2 adrenergic receptor and Beta-3 adrenergic receptor are activated by Epinephrine and L-Noradrenaline. Conventional signaling is accomplished via G-protein alpha-s/ Adenylate cyclase that leads to Cyclic AMP production and activation of PKA-reg (cAMP-dependent) and PKA-cat (cAMP-dependent) [1]. AKAP6 is an anchor protein that enables PKA-cat (cAMP-dependent) 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 (cAMP-dependent) phosphorylates Phospholamban. Phosphorylation of Phospholamban is believed to release its tonic inhibition of Ca-ATPase1 and (Ca-ATPase2 and to Ca('2+) flux to endoplasmatic reticulum. Ca('2+) flux from cytoplasm accelerates relaxation of cardiac muscle [5].

Also PKA-cat (cAMP-dependent) phosphorylates Troponin I, cardiac. Phosphorylation prevents Troponin I, cardiac interaction with Troponin C, cardiac and leads to weaker Ca('2+) binding and thereby to relaxation of cardiac muscle [5], [6]. PKA-cat (cAMP-dependent)-mediated phosphorylation of Troponin I, cardiac is antagonized by dephosphorylation by PP2A catalytic [7].

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

Activated by Beta-1 adrenergic receptor and Beta-2 adrenergic receptor, PKA-cat (cAMP-dependent) participates in activation of L-type Ca(II) channel, alpha 1C subunit. Ca('2+) current via (L-type Ca(II) channel, alpha 1C subunits 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, alpha 1C subunit and Phospholamban [5]. PKA-cat (cAMP-dependent)-mediated activation of PDE4D and PDE3A leads to decrease in Cyclic AMP level in cytoplasm due to conversion of Cyclic AMP to AMP by PDE [5], [9], [10].

PKA-cat (cAMP-dependent) activated by Beta-2 adrenergic receptor and Beta-3 adrenergic receptor presumably phosphorylates BETA-PIX [11] which in turn activates CDC42/ MEKK4(MAP3K4)/ MEK6(MAP2K6) and MEK3(MAP2K3)/ p38 MAPK [12], [13], leading to relaxation relaxation of cardiac muscle [12]. In white/brown adipocytes and intestinal smooth muscle cells, the above ivents lead to activation of PPARGC1 (PGC1-alpha)/ PPAR-gamma. PPAR-gamma is in a complex with PPAR-gamma/RXR-alpha that participates in transcriptional activation of UCP1. UCP1 participates in physiological processes of nonshivering thermogenesis in brown adipocites and in relaxation of intestinal smooth muscle cells [13], [14].

PKA-cat (cAMP-dependent) 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 (see lipid catabolic process) [15].



Objects list:

AKAP6 A-kinase anchor protein 6
AMP Chemical IUPAC name [(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate
Adenylate cyclase Adenylate cyclase Protein group
BETA-PIX Rho guanine nucleotide exchange factor 7
Beta-1 adrenergic receptor Beta-1 adrenergic receptor
Beta-2 adrenergic receptor Beta-2 adrenergic receptor
Beta-3 adrenergic receptor Beta-3 adrenergic receptor
CDC42 Cell division control protein 42 homolog
Ca('2+) Chemical IUPAC name calcium(+2) cation
Ca('2+) Chemical IUPAC name calcium(+2) cation
Ca-ATPase1 Sarcoplasmic/endoplasmic reticulum calcium ATPase 1
Ca-ATPase2 Sarcoplasmic/endoplasmic reticulum calcium ATPase 2
CaMK II CaMK II Complex
Calmodulin Calmodulin
Cyclic AMP Chemical IUPAC name (1S,6R,8R,9R)-8-(6-amino-8-bromopurin-9-yl)-3-hydroxy-3-oxo-2,4,7-trioxa-35-phosphabicyclo[4.3.0]nonan-9-ol
Epinephrine Chemical IUPAC name 4-[(1R)-1-Hydroxy-2-methylaminoethyl]benzene-1,2-diol
G-protein alpha-s Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
L-Noradrenaline Chemical IUPAC name 4-[(1R)-2-Amino-1-hydroxyethyl]benzene-1,2-diol
L-type Ca(II) channel, alpha 1C subunit Voltage-dependent L-type calcium channel subunit alpha-1C
LIPS Hormone-sensitive lipase
MEK3(MAP2K3) Dual specificity mitogen-activated protein kinase kinase 3
MEK6(MAP2K6) Dual specificity mitogen-activated protein kinase kinase 6
MEKK4(MAP3K4) Mitogen-activated protein kinase kinase kinase 4
PDE3A cGMP-inhibited 3',5'-cyclic phosphodiesterase A
PDE4D cAMP-specific 3',5'-cyclic phosphodiesterase 4D
PHK alpha (muscle) Phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform
PHK gamma (muscle) Phosphorylase b kinase gamma catalytic chain, skeletal muscle isoform
PKA-cat (cAMP-dependent) Protein kinase, cAMP-dependent, catalytic Protein group
PKA-reg (cAMP-dependent) Cyclic AMP-dependent protein kinase A regulatory subunit Protein group
PP2A catalytic Protein phosphatase 2A catalytic Protein group
PPAR-gamma Peroxisome proliferator-activated receptor gamma
PPAR-gamma/RXR-alpha PPAR-gamma/RXR-alpha Complex
PPARGC1 (PGC1-alpha) Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
PYGM Glycogen phosphorylase, muscle form
Perilipin Perilipin-1
Phospholamban Cardiac phospholamban
Ryanodine receptor 2 Ryanodine receptor 2
Troponin C, cardiac Troponin C, slow skeletal and cardiac muscles
Troponin I, cardiac Troponin I, cardiac muscle
UCP1 Mitochondrial brown fat uncoupling protein 1
p38 MAPK p38 mitogen-activated protein kinase Protein group

References:

  1. Skeberdis VA
    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
  4. Kuschel M, Zhou YY, Cheng H, Zhang SJ, Chen Y, Lakatta EG, Xiao RP
    G(i) protein-mediated functional compartmentalization of cardiac beta(2)-adrenergic signaling. The Journal of biological chemistry 1999 Jul 30;274(31):22048-52
  5. Saucerman JJ, McCulloch AD
    Cardiac beta-adrenergic signaling: from subcellular microdomains to heart failure. Annals of the New York Academy of Sciences 2006 Oct;1080:348-61
  6. Kuschel M, Zhou YY, Spurgeon HA, Bartel S, Karczewski P, Zhang SJ, Krause EG, Lakatta EG, Xiao RP
    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
  8. Chen-Izu Y, Xiao RP, Izu LT, Cheng H, Kuschel M, Spurgeon H, Lakatta EG
    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

  1. Skeberdis VA
    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
  4. Kuschel M, Zhou YY, Cheng H, Zhang SJ, Chen Y, Lakatta EG, Xiao RP
    G(i) protein-mediated functional compartmentalization of cardiac beta(2)-adrenergic signaling. The Journal of biological chemistry 1999 Jul 30;274(31):22048-52
  5. Saucerman JJ, McCulloch AD
    Cardiac beta-adrenergic signaling: from subcellular microdomains to heart failure. Annals of the New York Academy of Sciences 2006 Oct;1080:348-61
  6. Kuschel M, Zhou YY, Spurgeon HA, Bartel S, Karczewski P, Zhang SJ, Krause EG, Lakatta EG, Xiao RP
    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
  8. Chen-Izu Y, Xiao RP, Izu LT, Cheng H, Kuschel M, Spurgeon H, Lakatta EG
    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

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