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. They participate in many physiological processes via different pathways. One of the best studied alpha-1 adrenergic receptors-stimulated pathways is a Mitogen-activated protein kinase 1 and 3 (ERK1/2) activation [1], [2].

Natural catecholamines, Adrenaline, and Noradrenaline, activate alpha-1 adrenergic receptors [1], [3]. The activated receptors interact with different Guanine nucleotide binding proteins (G-proteins). All three receptors interact with G-protein alpha-q and G-protein alpha-11 [4]. Alpha-1A adrenergic receptor and Alpha-1B adrenergic receptor couple with G-protein alpha-14 [5]. Alpha-1B adrenergic receptor and Alpha-1D adrenergic receptor interact with Transglutaminase 2 (TGM2) [6], [7], [8]. Alpha-1B adrenergic receptor couples with G-protein alpha-15 [5] and G-protein alpha activating activity 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) [1], [5], [9]. TGM2 activate Phospholipase C delta 1 (PLC-delta1) [8], [10]. PLC-beta1 and PLC-delta1 hydrolyze Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) to produce Inositol 1,4,5-trisphosphate (IP3) and 1,2-diacyl-glycerol (DAG) [8], [11].

DAG and IP3 participate in activation of Ca('2+)-dependent Protein kinase C alpha (PKC-alpha) [12], Ca('2+)-independent Protein kinases C delta and epsilon (PKC-delta and PKC-epsilon) [1], [13], [14] and mobilization of intracellular Ca('2+). All these pathways may lead to activation of cell growth and proliferation.

Cytosolic Ca('2+) activates Calmodulin / Calcium/calmodulin-dependent protein kinase II (CaMK II)/ PTK2B protein tyrosine kinase 2 beta (Pyk2(FAK2))/ v-src sarcoma viral oncogene homolog (c-Src)/ SHC transforming protein (Shc)/ Son of 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 kinases 1 and 2 ((MEK1(MAP2K1) and MEK2(MAP2K2))/ Mitogen-activated protein kinase 1 and 3 (ERK1/2) pathway [13], [15].

G-protein alpha-q-stimulated PKC-alpha and PKC-epsilon may activate Erk cascade in H-Ras-independent manner (e.g., via phosphorylation of c-Raf-1) [16], [17]. On the other hand PKC-delta and PKC-epsilon may activate Erk cascade in H-Ras-independent manner via phosphorylation of Pyk2(FAK2) [16], [18], [19].

Alpha-1 adrenergic receptors-dependent ERK1/2 activation may also be realized via 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 SHC transforming protein (Shc)/ Son of sevenless homolog (SOS)/ H-Ras [21].

Activated PI3K catalyzes transformation of PtdIns(4,5)P2 into Phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3). Presumably, then PtdIns(3,4,5)P3 activates Shc / SOS / H-Ras. After that, H-Ras activates c-Raf-1 / MEK1(MAP2K1), MEK2(MAP2K2))/ ERK1/2 [15], [20], [21].

Activated ERK1/2 phosphorylate V-fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos) and Jun oncogene (c-Jun), thus activating cell growth and proliferation [1], [13], [21].

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, may facilitate activation of Ca('2+) -dependent PKC-alpha, thus creating a positive feedback loop. CaMK II may activates L-type Ca(II) channel as well[27].

References:

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