Development Activation of ERK by Alpha-1 adrenergic receptors
Activation of ERK by Alpha-1 adrenergic receptors
Subtype alpha-1 adrenergic receptors consists of Alpha-1A adrenergic receptor,Alpha-1B adrenergic receptor and Alpha-1D adrenergic receptor. Theyparticipate in many physiological processes via different pathways. One of the beststudied alpha-1 adrenergic receptors-stimulated pathways is a Mitogen-activated proteinkinase 1 and 3 ( ERK1/2 ) activation [1], [2].
Natural catecholamines, Adrenaline, and Noradrenaline, activate alpha-1adrenergic receptors [1], [3]. The activated receptors interactwith different Guanine nucleotide binding proteins (G-proteins). All three receptorsinteract with G-protein alpha-q and G-protein alpha-11 [4].Alpha-1A adrenergic receptor and Alpha-1B adrenergic receptor couple withG-protein alpha-14 [5]. Alpha-1B adrenergic receptor andAlpha-1D adrenergic receptor interact with Transglutaminase 2 ( TGM2 )[6], [7], [8]. Alpha-1B adrenergic receptorcouples with G-protein alpha-15 [5] and G-protein alpha activatingactivity polypeptide O ( G-protein alpha-o ) [4].
G-protein alpha-11, G-protein alpha-q, G-protein alpha-14,G-protein alpha-15 activate Phospholipase C beta 1 ( PLC-beta1 ) [5], [1], [9]. TGM2 activate Phospholipase C delta1 ( PLC-delta1 ) [10], [8]. PLC-beta1 andPLC-delta1 hydrolyze Phosphatidylinositol-4,5-bisphosphate ( PtdIns(4,5)P2) to produce Inositol 1,4,5-trisphosphate ( IP3 ) and 1,2-diacyl-glycerol (DAG ) [11], [8].
DAG and IP3 participate in activation of Ca('2+) -dependentProtein kinase C alpha ( PKC-alpha ) [12], Ca('2+) -independentProtein kinases C delta and epsilon ( PKC-delta and PKC-epsilon ) [13], [1], [14] and mobilization of intracellularCa('2+). All these pathways may lead to activation of cell growth andproliferation.
Cytosolic Ca('2+) activates Calmodulin/ Calcium/calmodulin-dependentprotein kinase II ( CaMK II )/ PTK2B protein tyrosine kinase 2 beta (Pyk2(FAK2) )/ v-src sarcoma viral oncogene homolog ( c-Src )/ SHCtransforming protein ( Shc )/ Son of sevenless homolog ( SOS )/ v-Ha-rasHarvey rat sarcoma viral oncogene homolog ( H-Ras )/ v-raf-1 murine leukemiaviral oncogene homolog 1 ( c-Raf-1 )/ Mitogen-activated protein kinase kinases 1and 2 (( MEK1(MAP2K1) and MEK2(MAP2K2) )/ Mitogen-activated protein kinase1 and 3 ( ERK1/2 ) pathway [15], [13].
G-protein alpha-q -stimulated PKC-alpha and PKC-epsilon mayactivate Erk cascade in H-Ras -independent manner (e.g., via phosphorylation ofc-Raf-1) [16], [17]. On the other hand PKC-delta andPKC-epsilon may activate Erk cascade in H-Ras -independent manner viaphosphorylation of Pyk2(FAK2) [16],[18], [19].
Alpha-1 adrenergic receptors-dependent ERK1/2 activation may also be realizedvia Phosphoinositide-3-kinase ( PI3K ) [20], [21].c-Src can activate PI3K reg class IA (p85-alpha)/ PI3K cat class IA(p110-beta) directly [21], [22], [23] or via SHCtransforming protein ( Shc )/ Son of sevenless homolog ( SOS )/H-Ras [21].
Activated PI3K catalyzes transformation of PtdIns(4,5)P2 in toPhosphatidylinositol-3,4,5-trisphosphate ( PtdIns(3,4,5)P3 ). Presumably, thenPtdIns(3,4,5)P3 activates Shc/ SOS/ H-Ras. After that,H-Ras activates c-Raf-1/ MEK1(MAP2K1), MEK2(MAP2K2) )/ERK1/2 [20], [15], [21].
Activated ERK1/2 phosphorylate V-fos FBJ murine osteosarcoma viral oncogenehomolog ( c-Fos ) and Jun oncogene ( c-Jun ), thus activating cell growthand proliferation [21], [13], [1].
Moreover, PKC-alpha, probably phosphorylates Ca2+ channels (for example,Calcium channel, voltage-dependent L type ( L-type Ca(II) channel ) [24], [25]) and this increase extracellular Ca('2+) entry [26]. High level of Ca('2+) influence cell contraction [2]. Also,high level of Ca('2+), which was achieved due Ca2+ channels activation, mayfacilitate activation of Ca('2+) -dependent PKC-alpha, thus creating apositive feedback loop. CaMK II may activates L-type Ca(II) channel aswell[27].
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