Cellular and molecular mechanisms underlying nicotine induced upregulation of alpha 7 nicotinic acet...

مرکز و کتابخانه مطالعات اسلامی به زبان های اروپایی

منو

" Cellular and molecular mechanisms underlying nicotine induced upregulation of alpha 7 nicotinic acetylcholine receptor expressed in xenopus oocytes: The role of CA2+ and CA2+-dependent signaling pathways "
Mohammad Faridul Islam Farley, Joseph

Document Type	:	Latin Dissertation
Language of Document	:	English
Record Number	:	803535
Doc. No	:	TL48328
Call number	:	‭1706911511;‮ ‬3712458‬
Main Entry	:	Gomes, Jorge Costa
Title & Author	:	Cellular and molecular mechanisms underlying nicotine induced upregulation of alpha 7 nicotinic acetylcholine receptor expressed in xenopus oocytes: The role of CA2+ and CA2+-dependent signaling pathways\ Mohammad Faridul IslamFarley, Joseph
College	:	Indiana University
Date	:	2015
Degree	:	Ph.D.
field of study	:	Neuroscience
student score	:	2015
Page No	:	212
Note	:	Committee members: Hohmann, Andrea; Mackie, Ken; Rebec, George
Note	:	Place of publication: United States, Ann Arbor; ISBN=978-1-321-89307-6
Abstract	:	Neuronal nicotinic-acetylcholine receptors (nAChRs) (e.g., α4β2, α7 Rs) appear to play critical roles in learning, memory, and various neuropathologies including nicotine addiction. Nicotine-upregulation of α7 Rs is thought to play a significant role in these phenomena. But whether nicotine-upregulation of α7 Rs in fact occurs, and the nature of its underlying mechanism(s), are largely unknown. Previous lt;igt;in vitrolt;/igt; studies of α7 nAChRs heterologously expressed in lt;igt;Xenopuslt;/igt; oocytes failed to observe nicotine-upregulation. These failures might have been due to incomplete removal of nicotine from the recording media, as a result of its intracellular accumulation and subsequent slow release from the oocytes, resulting in desensitization of α7 Rs during functional assays. Our GC/MS measurements confirmed that this was likely to be the case. In our experiments, 12-14 hr exposure to nicotine (100 µM), followed by extensive 7 hr washout yielded reliable, statistically-significant ~2-fold increases in macroscopic α7 R currents (as determined by two-electrode voltage clamp) and α7-protein (by Western blot). Less-extensive washout failed to produce upregulation; instead, desensitization was observed. Nicotine-upregulation was also correlated with the level of surface expression of α7 Rs, and did not involve new protein synthesis. Similar to nicotine, methyllycaconitine, a cell-permeable competitive antagonist of α7 Rs, as well as carbachol, a membrane-impermeable agonist, also produced upregulation, suggesting that ligand-binding to α7 Rs (but not activation of the receptors) was critical. Nicotine-upregulation of α7 Rs was unaffected by removal of extracellular Calt;supgt;2+lt;/supgt;. However, intracellular Calt;supgt;2+lt;/supgt; chelation completely blocked upregulation. Several Calt;supgt;2+lt;/supgt; -dependent intracellular signaling pathways appeared to be critical for nicotine -upregulation: PP2B/calcineurin (inhibited by cyclosporine A), serine-threonine protein kinase-activity (inhibited by the compound H7), and perhaps one or more PKC isozymes (activated by a phorbol ester). In contrast, although protein tyrosine kinase (PTK) activity (inhibited by genistein) had a great influence on basal α7 currents [via positive allosteric modulatory (PAM-) and non-PAM effects], PTKs did not seem to participate in nicotine-produced upregulation. Tests of the potential contribution to nicotine-upregulation of lt;igt;cislt;/igt;-Golgi/ER quality control mechanisms (by the COPI-inhibitor CI-976) and α7-GPC signaling (via Gq/11; by a Substance-P analog) were inconclusive. These compounds strongly inhibited basal α7 currents.
Subject	:	Neurosciences; Physiology
Descriptor	:	Biological sciences;Alpha 7;Calcium;Nicotinic acetylcholine receptor;Upregulation
Added Entry	:	Farley, Joseph
Added Entry	:	NeuroscienceIndiana University
	:
	:
	:
	:
	: