Development Alpha-2 adrenergic receptor activation of ERK
Alpha-2 adrenergic receptor activation of ERK Alpha-2A adrenergic receptor, Alpha-2B adrenergic receptor, andAlpha-2C-1 adrenergic receptor participate in activation of Mitogen-activatedprotein kinases 1 and 3 ( ERK1/2 ) via different ways . Alpha-2A adrenergic receptor activates Phospholipase C beta 3 or 2 (PLC-beta3 or PLC-beta2) when complex Guanine nucleotide binding protein (Gprotein) beta and gamma ( G-protein beta/gamma ) is released from the trimericcomplex with G-protein alpha-i family (presumably by G-protein alpha-i2 ), . PLC-beta3 and PLC-beta2 may to hydrolyzePhosphatidylinositol-4,5-Bisphosphate ( PtdIns(4,5)P2 ) and produce1,2-diacyl-glycerol ( DAG ) and Inositol 1,4,5-trisphosphate ( IP3 ).IP3 activates Inositol 1,4,5-triphosphate receptor type 3 ( IP3 receptor ),which causes Ca('2) release from intracellular compartments. As a result ofactivation of adrenergic receptor, elevated cytosolic Ca('2) levels lead toactivation of Calmodulin/ most likely Calcium/calmodulin-dependent protein kinaseII ( CaMK II )/ PTK2B protein tyrosine kinase 2 beta ( Pyk2(FAK2) )/v-src sarcoma viral oncogene homolog ( c-Src )/ SHC transforming protein 1 (Shc )/ Growth factor receptor-bound protein 2 ( GRB2 )/ son of sevenlesshomolog ( SOS )/ v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras )/ v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/Mitogen-activated protein kinase kinase 1 and 2 ( MEK1 and MEK2 )/Erk . Also, activation of ERK cascade by all three Alpha-2 adrenergicreceptors is accomplished by stimulation of Arachidonic acid production viaDAG. DAG is catalyzed by Diacylglycerol lipase alpha and beta ( DGL-alphaand DGL-beta ) to 2-arachidonoylglycerol, which gets converted byMonoglyceride lipase to Arachidonic acid. Arachidonic acid is thenconverted by Cytochrome P450 (by, for instance, Cytochrome P450 family 2 subfamily Cpolypeptide 8 ( CYP2C8 )) to 14,15-epoxyeicosatrienoic acid ( 14,15-EET ),which activates c-Src. c-Src may phosphorylate matrix metalloproteinases, forexample ADAM metallopeptidase domain 12 ( ADAM12 ). ADAM12, in turn,cleaves Heparin-binding EGF-like growth factor ( HB-EGF ) leading totransactivation of Epidermal growth factor receptor ( EGFR ). EGFR thenactivates Shc- and GRB2 -mediated ERK cascade activation . In addition, Alpha-2A and Alpha-2C-1 adrenergic receptors, afteractivation of c-Src, can activate Shc/ GRB2/ SOS withoutEGFR-transactivation . Also, all three Alpha-2 adrenergic receptors stimulate v-akt murine thymomaviral oncogene homolog ( AKT(PKB )) that is thought to activate ERK2 andERK1. AKT(PKB ) may act via EGFR/ Phosphoinositide-3-kinase (PI3K)/ PtdIns(3,4,5)P3/ possibly via GRB2-associated binding protein 1 (GAB1 ) or directly/ 3-phosphoinositide dependent protein kinase-1 ( PDK(PDPK1 )/ AKT. Alpha-2A and Alpha-2C-1 adrenergic receptorsare also able to activate Phosphoinositide-3-kinase, regulatory subunit 1 (p85 alpha) (PI3K reg class IA (p85-alpha) ) via c-Src without EGFRtransactivation , , . Moreover, Alpha-2B adrenergic receptor participates in ERK activationvia extracellular Ca('2+) dependent Phospholipase A2 ( cPLA2 ) activation,which in turn lead to Arachidonic acid production and to the above-describedERK cascade activation via Shc . Due to ERK activity, adrenergic receptors influence cell growth andproliferation , . Furthermore, in nerve cells, ERKactivates Jun oncogene ( c-Jun ) and participates in cell differentiation .