Apoptosis and survival - nAChR in apoptosis inhibition and cell cycle progression

nAChR in apoptosis inhibition and cell cycle progression

Nicotinic acetylcholine receptors (nAChR) are pentameric proteins comprising either combinations of two different types of subunit (nAChR alpha and nAChR beta) or five copies of the same alpha subunit symmetrically arranged around a central ion pore [1].

nAChR alpha-7 form a signaling complex with Fyn and PI3K reg class IA (p85). PI3K reg class IA (p85) is a regulatory subunit of PI3K cat class IA and may activate the latter one upon nAChR alpha-7 stimulation by Nicotine. PI3K cat class IA is an enzyme that converts Phosphatidylinositol 4,5-biphosphate (PtdIns(4,5)P2) to Phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3). PtdIns(3,4,5)P3 is a second messenger that directly binds via pleckstrin homology (PH) domen with V-akt murine thymoma viral oncogene homolog (AKT(PKB)) leading to activation of latter one by 3-phosphoinositide dependent protein kinase-1 (PDK(PDPK1)). PI3K/AKT pathway plays important role in cell proliferation and survival. AKT(PKB) activates FK506 binding protein 12-rapamycin associated protein 1 (mTOR), apparently through Tuberin/ GTP-binding protein Ras homolog enriched in brain (RHEB) pathway. mTOR phosphorylates and inactivates Eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1). mTOR also activates Ribosomal protein 6S kinase 70kDa, polypeptide 1 (p70S6 kinase1) by phosphorylation. AKT(PKB) inhibits apoptosis through Forkhead box O1 (FKHR) inactivation and phosphorylation, it also phosphorylates and inactivates glycogen synthase kinase 3 alpha (GSK3 alpha) and Glycogen synthase kinase 3 beta (GSK3 beta) [2], [3], [4], [5].

Nicotine stimulation causes the assembly of oligomeric complexes involving Beta-arrestin1, V-src sarcoma viral oncogene homolog (c-Src), and nAChRs, facilitating the activation of c-Src. This leads to the phosphorylation and activation of V-raf-leukemia viral oncogene 1 (Raf-1) which binds to Rb protein and therefore stimulates cell cycle progression [6].

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