Translation Translation regulation by Alpha-1 adrenergic receptors

Translation regulation 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.Noradrenaline -activated alpha-1 adrenergic receptors participate in manyphysiological processes including translation activation [1], [2], [2]

These adrenergic receptors activate different Guanine nucleotide binding proteins(G-proteins). For example, all three receptors interact with G-protein alpha-q andG-protein alpha-11 [3], [4], [1]. Alpha-1Badrenergic receptor acts through G-protein beta/gamma of pertussistoxin-sensitive Alpha activating activity polypeptide O ( G-protein alpha-o )[3], [5]. Then, G-proteins activate Phospholipase C beta 1 (PLC-beta1 ) [6]. PLC-beta1 hydrolyzesPhosphatidylinositol-4,5-bisphosphate ( PtdIns(4,5)P2 ) to produce Inositol1,4,5-trisphosphate ( IP3 ) and 1,2-diacyl-glycerol ( DAG ).

IP3 interacts with Inositol 1,4,5-triphosphate receptor type 3 ( IP3receptor ) of the endoplasmic reticulum, and this leads to Ca('2+) release.Elevated Ca('2+) level 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 ) [7]. c-Src can activate Phosphoinositide-3-kinase, regulatory subunit 1(alpha) ( PI3K reg class IA (p85-alpha) )/ PI3K cat class IA (p110-beta)directly [4], [8], [9] or via SHC (Src homology 2domain containing) transforming protein 1 ( Shc )/ Son of sevenless homolog (SOS )/ v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras ) [4].

Activated PI3K catalyzes transformation of PtdIns(4,5)P2 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 v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1)/ Mitogen-activated protein kinase kinases 1 and 2 ( MEK1(MAP2K1) andMEK2(MAP2K2) )/ Mitogen activated protein kinase 1 ( ERK2(MAPK1) ) [10], [1].

In addition, Protein kinase C, delta and epsilon ( PKC-delta andPKC-epsilon ) are believed to be activated by DAG [5], [11] and can stimulate Pyk2(FAK2)/ PI3K/ ERK2(MAPK1) asdescribed [10], [8], [1] .

ERK2(MAPK1) activates Tuberous sclerosis 2 ( Tuberin ) [12]/ Ras homolog enriched in brain ( RHEB2 )/ FK506 binding protein 12-rapamycinassociated protein 1 ( mTOR )/ Ribosomal protein S6 kinase 70kDa polypeptide 1and 2 ( p70 S6 kinase1 and p70 S6 kinase2 )/ Eukaryotic elongationfactor-2 kinase ( eEF2K )/ Eukaryotic translation elongation factor 2 (eEF2 ).

Also, mTOR activates Eukaryotic translation initiation factor 4E bindingprotein 1 ( 4E-BP1 ) release from Eukaryotic translation initiation factor 4E (eIF4E ), that, in turn, activates group Eukaryotic translation initiation factor 4gamma ( eIF4G1/3 )/ Eukaryotic translation initiation factor 4A ( eIF4A )[10], [1], [13]. PKC-delta seems to have moreinfluence on the mTOR activation, and have excusive influence on 4E-BP1[11], in this case it phosphorylates 4E-BP1 synergistically withmTOR [14].

Moreover, Alpha-1A adrenergic receptor may participate in protein synthesisstimulation via Pyk2(FAK2) )/ c-Src/ Phospholipase D1 and D2 pathway (PLD1 and PLD2 ) [15], [16]. PLD1 andPLD2 participate in reaction of Phosphatidic acid production, which thenactivates mTOR, thus stimulating translation via eEF2 and/or eIF4A[16], [13].

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