Development Beta-adrenergic receptors signaling via cAMP
Beta-adrenergic receptors signaling via cAMP
Beta-1, Beta-2 and Beta-3 adrenergic receptors are activated byAdrenaline and Noradrenaline. Conventional signaling is accomplished viaGNAS complex locus ( G-protein alpha-s )/ Adenylate cyclase that leads toAdenosine 3',5'-cyclic phosphate ( cAMP ) production and activation of Proteinkinase cAMP-dependent regulatory and catalytic ( PKA-reg (cAMP-dependent) andPKA-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 belocalized to plasma membrane, unlike that of Beta-1 adrenergic receptor [4].
Beta-1 adrenergic receptor coupled PKA-cat phosphorylatesPhospholamban. Phosphorylation of Phospholamban is believed to release itstonic inhibition of ATPase Ca++ transporting cardiac muscle fast twitch 1 and slowtwitch 2 ( Ca-ATPase1 and Ca-ATPase2 ) and to Ca('2) cytosol flux toendoplasmatic reticulum. Ca('2) flux from cytoplasm accelerates relaxation ofcardiomyocytes [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 torelaxation of cardiac myocytes. [6], [5]. PKA-cat-mediated phosphorylation of Troponin I is antagonized by dephosphorylation byProtein phosphatase 2 catalytic subunit ( PP2A catalytic ) [7].
PKA-cat phosphorylation of Ryanodine receptor 2 leads to elevatedCa('2+) flux to cytoplasm. Elevated Ca('2+) in cardiac muscles normally haschronotropic effect [3], [5]
PKA-cat, e.g., in cardiomyocytes, activates Phosphorylase kinase alpha 1 andgamma 1 ( PHK alpha (muscle) and PHK gamma (muscle) )/ Phosphorylaseglycogen muscle ( PYGM ) and this leads to acceleration of glycogen breakdown rate[6], [5].
Activated by Beta-1 and Beta-2 adrenergic receptors, PKA-catparticipates 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 contractionof cardiomyocytes [4], [8]. Elevated level of Ca('2) incardiomyocytes leads to activation of ( Calmodulin )/ ( CaMK II ). CaMKII 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 cAMPlevel in cytoplasm due to conversion of cAMP to AMP by PDE [9], [10], [5].
PKA-cat activated by Beta-2 and Beta-3 adrenergic receptorspresumably 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) andMEK3(MAP2K3) )/ Mitogen-activated protein kinase 14 ( p38 MAPK ) [12], [13], leading to relaxation of cariomyocytes [12]. Inwhite/brown adipocytes and intestinal smooth muscle cells, the above ivents lead toactivation 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 ofUncoupling protein 1 ( UCP1 ). UCP1 participates in physiological processesof nonshivering thermogenesis in brown adipocites and in relaxation of intestinal smoothmuscle cells [13], [14].
PKA-cat activated by Beta-3 adrenergic receptor phosphorylates Lipasehormone-sensitive ( LIPS ) and Perilipin, the latter being a facilitatorof LIPS activity. This way, Beta-3 adrenergic receptor stimulates lipolysis[15].
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