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Development ACM2 and ACM4 activation of ERK

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Development ACM2 and ACM4 activation of ERK

ACM2 and ACM4 activation of ERK

Cholinergic receptor muscarinic 2 and 4 ( ACM2 and ACM4 ) act viaGuanine nucleotide binding proteins (G-protein) of G-protein alpha-i family. ACM2can activate all representatives of the family and ACM4 acts exclusively viaG-protein alpha-o and G-protein alpha-i2 [1]. A natural agonist ofACM2 and ACM4 is acetylcholine.

ACM2 and ACM4 via G-protein beta/gamma released aftertransformation of G-protein alpha-i family activates Phosphoinositide-3-kinasecatalytic gamma polypeptide ( PI3K cat class IB (p110-gamma) )/Phosphatidylinositol-3,4,5-trisphosphate ( PtdIns(3,4,5)P3 )/ SHC transformingprotein 1 ( Shc )/ Growth factor receptor-bound protein 2 ( GRB2 )/ Sonof sevenless homolog ( 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 2 and 1 ( MEK2 and MEK1 ) cascade.MEK1 and 2 in turn activate Mitogen-activated protein kinase 1 and 3 (ERK1/2 ) [2], [3].

In addition, ACM2 stimulates ERK1/2 activation in Protein kinase C (PKC ) and/or Ca('2) -dependent manner. Exactly mechanism this cascade isunknown. It may be realized via Phospholipase C beta ( PLC-beta ). PLC-betaproduces Inositol 1,4,5-trisphosphate ( IP3 ) and 1,2-diacyl-glycerol ( DAG). IP3 stimulates Ca('2) releasing from endoplasmatic reticulum. Ca('2)cytosol may activate Ca('2) cytosol/ Calmodulin/Calcium/calmodulin-dependent protein kinase II ( CaMK II )/ PTK2B proteintyrosine kinase 2 beta ( Pyk2(FAK2) ) [4], [5], [6].

In addition, DAG may participate in activation of PKC (e.g.,PKC-alpha, PKC-delta or PKC-epsilon [7]), which mayalso stimulate ( Pyk2(FAK2).

It is known that ACM2 can transactivate Epidermal growth factor receptor (EGFR ) via FYN oncogene related to SRC FGR and YES ( Fyn ) [8]. It is possible that Fyn is activated by Pyk2(FAK2), as it wasshown for other receptors [9]. Fyn binds Epidermal growth factorreceptor ( EGFR ) and probably leads to it's activation by autophosphorylation.Transactivated EGFR then leads to a common ERK pathway via Shc/GRB2/ SOS/ H-Ras/ c-Raf-1/ MEK1 and 2/ERK1/2 [8].

Also, ACM2 activates RAP1 GTPase activating protein ( Rap1GAP1 ) viaG-protein alpha-i family, which prevents the inhibitory action of RAP1A member ofRAS oncogene family ( RAP-1A ) on c-Raf-1 and thereby promotes activationof ERK1/2 [10].

ACM2 and ACM4 dependent activation of ERK 1/2 maintainLong-term potentiation of neurons [5] via Ribosomal protein S6 kinase 90kDapolypeptide 1 ( p90RSK1 ) [11]/ cAMP responsive element bindingprotein 1 ( CREB1 )/ Early growth response 1 ( EGR1 ) [12].This also influences cell proliferation via p90RSK1/ CREB1/ v-fos FBJmurine osteosarcoma viral oncogene homolog ( c-Fos ) [13] and ELK1member of ETS oncogene family ( Elk-1 ) [5]. ACM2 activationof ERK participates in chemotactic cell migration [3] and in colonsmooth muscle cell contraction via inhibitory phosphorylation of Caldesmon, whichblocks Myosin ATPase [14].