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:
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