Translation - Translation regulation by Alpha-1 adrenergic receptors

Translation regulation by Alpha-1 adrenergic receptors

Subtype alpha-1 adrenergic receptors consist of Alpha-1A adrenergic receptor, Alpha-1B adrenergic receptor and Alpha-1D adrenergic receptor. Noradrenaline-activated alpha-1 adrenergic receptors participate in many physiological processes, e.g., in translation activation [1], [2]

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

IP3 interacts with Inositol 1,4,5-triphosphate receptor type 3 (IP3 receptor) of the endoplasmic reticulum, and this leads to Ca('2+) release. Elevated Ca('2+) level 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) [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 2 domain 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 to Phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3). Presumably, then PtdIns(3,4,5)P3 then activates Shc / SOS / H-Ras. H-Ras then activates 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 (ERK2(MAPK1)) [1], [10].

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

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

Also, mTOR activates Eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) release from Eukaryotic translation initiation factor 4E (eIF4E) that in turn activates group Eukaryotic translation initiation factor 4 gamma (eIF4G1/3)/ Eukaryotic translation initiation factor 4A (eIF4A) [1], [10], [13]. PKC-delta seems participate in activation of mTOR and inhibition of 4E-BP1 [11]. PKC-delta phosphorylates 4E-BP1 synergistically with mTOR [14].

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

References:

1. Wang L, Proud CG
   Ras/Erk signaling is essential for activation of protein synthesis by Gq protein-coupled receptor agonists in adult cardiomyocytes. Circulation research 2002 Nov 1;91(9):821-9
2. Zhang Y, Yan J, Chen K, Song Y, Lu Z, Chen M, Han C, Zhang Y
   Different roles of alpha1-adrenoceptor subtypes in mediating cardiomyocyte protein synthesis in neonatal rats. Clinical and experimental pharmacology & physiology 2004 Sep;31(9):626-33
3. Gurdal H, Seasholtz TM, Wang HY, Brown RD, Johnson MD, Friedman E
   Role of G alpha q or G alpha o proteins in alpha 1-adrenoceptor subtype-mediated responses in Fischer 344 rat aorta. Molecular pharmacology 1997 Dec;52(6):1064-70
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   Contrasting signaling pathways of alpha1A- and alpha1B-adrenergic receptor subtype activation of phosphatidylinositol 3-kinase and Ras in transfected NIH3T3 cells. Molecular endocrinology (Baltimore, Md.) 1999 Jan;13(1):3-14
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   Gq/11-coupled receptors and protein synthesis in rat cardiomyocytes: role of Gi-proteins and protein kinase C-isozymes. Naunyn-Schmiedeberg's archives of pharmacology 1999 Sep;360(3):301-8
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   Evidence for selective coupling of alpha 1-adrenergic receptors to phospholipase C-beta 1 in rat neonatal cardiomyocytes. The Journal of biological chemistry 2001 Oct 5;276(40):37341-6
7. Della Rocca GJ, van Biesen T, Daaka Y, Luttrell DK, Luttrell LM, Lefkowitz RJ
   Ras-dependent mitogen-activated protein kinase activation by G protein-coupled receptors. Convergence of Gi- and Gq-mediated pathways on calcium/calmodulin, Pyk2, and Src kinase. The Journal of biological chemistry 1997 Aug 1;272(31):19125-32
8. Gentili C, Morelli S, Russo De Boland A
   Involvement of PI3-kinase and its association with c-Src in PTH-stimulated rat enterocytes. Journal of cellular biochemistry 2002;86(4):773-83
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   Specific role for p85/p110beta in GTP-binding-protein-mediated activation of Akt. The Biochemical journal 2005 Dec 15;392(Pt 3):607-14
10. Wang L, Gout I, Proud CG
    Cross-talk between the ERK and p70 S6 kinase (S6K) signaling pathways. MEK-dependent activation of S6K2 in cardiomyocytes. The Journal of biological chemistry 2001 Aug 31;276(35):32670-7
11. Wang L, Rolfe M, Proud CG
    Ca(2+)-independent protein kinase C activity is required for alpha1-adrenergic-receptor-mediated regulation of ribosomal protein S6 kinases in adult cardiomyocytes. The Biochemical journal 2003 Jul 15;373(Pt 2):603-11
12. Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP
    Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 2005 Apr 22;121(2):179-93
13. Averous J, Proud CG
    When translation meets transformation: the mTOR story. Oncogene 2006 Oct 16;25(48):6423-35
14. Kumar V, Pandey P, Sabatini D, Kumar M, Majumder PK, Bharti A, Carmichael G, Kufe D, Kharbanda S
    Functional interaction between RAFT1/FRAP/mTOR and protein kinase cdelta in the regulation of cap-dependent initiation of translation. The EMBO journal 2000 Mar 1;19(5):1087-97
15. Rybkin II, Cross ME, McReynolds EM, Lin RZ, Ballou LM
    alpha(1A) adrenergic receptor induces eukaryotic initiation factor 4E-binding protein 1 phosphorylation via a Ca(2+)-dependent pathway independent of phosphatidylinositol 3-kinase/Akt. The Journal of biological chemistry 2000 Feb 25;275(8):5460-5
16. Ballou LM, Jiang YP, Du G, Frohman MA, Lin RZ
    Ca(2+)- and phospholipase D-dependent and -independent pathways activate mTOR signaling. FEBS letters 2003 Aug 28;550(1-3):51-6