Pathway Map Details
Development_Beta-adrenergic receptors signaling via cAMP
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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) ) . A kinase anchor protein 6 ( AKAP6 ) is an anchor protein that enables PKA-cat phosphorylation , . Beta-2 adrenergic receptor signaling appears to be localized to plasma membrane, unlike that of Beta-1 adrenergic receptor .
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 .
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. , . PKA-cat -mediated phosphorylation of Troponin I is antagonized by dephosphorylation by Protein phosphatase 2 catalytic subunit ( PP2A catalytic ) .
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 , .
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 , . Elevated level of Ca('2) in cardiomyocytes leads to activation of ( Calmodulin )/ ( CaMK II ). CaMK II phospholylates L-type Ca(II) channel and Phospholamban . 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 , , .
PKA-cat activated by Beta-2 and Beta-3 adrenergic receptors presumably phosphorylates Rho guanine nucleotide exchange factor 7 ( BETA-PIX )  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 ) , , leading to relaxation of cariomyocytes . 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 , .
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 .
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