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Signaling Mechanisms Underlying Nico...

Panchal, Jayharsh L.

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Signaling Mechanisms Underlying Nicotine-Induced Upregulation of α7 Nicotinic Acetylcholine Receptor (nAChR).

Record Type:	Electronic resources : Monograph/item
Title/Author:	Signaling Mechanisms Underlying Nicotine-Induced Upregulation of α7 Nicotinic Acetylcholine Receptor (nAChR)./
Author:	Panchal, Jayharsh L.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
Description:	262 p.
Notes:	Source: Dissertations Abstracts International, Volume: 81-11, Section: B.
Contained By:	Dissertations Abstracts International81-11B.
Subject:	Cellular biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27959458
ISBN:	9798644902217

Signaling Mechanisms Underlying Nicotine-Induced Upregulation of α7 Nicotinic Acetylcholine Receptor (nAChR).
Panchal, Jayharsh L.

Signaling Mechanisms Underlying Nicotine-Induced Upregulation of α7 Nicotinic Acetylcholine Receptor (nAChR). - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 262 p.

Source: Dissertations Abstracts International, Volume: 81-11, Section: B.

Thesis (Ph.D.)--Indiana University, 2020.

This item must not be sold to any third party vendors.

α7 nicotinic acetylcholine receptors (nAChRs) are the second most abundant nAChR in brain and have been implicated to play a role in nicotine addiction. Though upregulation of α7 nAChRs by nicotine (Nic) has been demonstrated previously, particularly in in vivo studies, the cellular and molecular mechanisms responsible for nic-upregulation are poorly understood. We have shown ~2-fold functional and numerical upregulation of α7 nAChRs in Xenopus oocytes following nicotine treatment. Previously, we found that the nic-upregulation of α7 nAChR was dependent upon intracellular calcium [Ca2+]i. These observations raise critical questions as to: 1) the source of the obligatory [Ca2+]i increases, and 2) the downstream cellular processes responsible for nic-upregulation. This dissertation addresses those issues, using a combination of genetic, pharmacological, protein chemistry, and electrophysiological/biophysical approaches. In various cell types, G-protein signaling regulates α7 nAChR function via modulation of [Ca2+]i. α7 nAChR subunits, in their transmembrane (TM3-TM4) cytosolic loop, contain a canonical G- protein binding cluster (GPBC). Here, we demonstrate a role for α7 nAChR/Gαq protein interaction in the activation of a PLC-β pathway leading to prolonged increases in [Ca2+]i that, ultimately, inhibits constitutive endocytic pathways to cause nic-upregulation of α7 nAChRs. Mutation at GPBC or inhibition of endogenous Gαq expression abrogated nic-upregulation of α7 Rs. Furthermore, when Gαq was exogenously co-expressed with α7 Rs, we saw ~2X upregulation. But when a dominant negative Gαq was co-expressed with α7, a significant attenuation of nic-upregulation of wt α7 Rs was observed. We also found that the calcineurin inhibitor cyclosporine A produced 2X-upregulation of wt α7 Rs and occluded nic-upregulation. Endocytic-inhibitors produced ~2X upregulation of both wt (and mutant) α7 Rs and occluded nic-upregulation. Brefeldin A (BFA) failed to affect nic-upregulation. Serine-threonine kinase and tyrosine kinase-phosphorylation events have generally inhibitory effects on forward trafficking of α7 Rs. Nic-upregulation was unaffected when serine-365 or tyrosine-442 was mutated, further supporting the hypothesis that nic-upregulation of α7 arises from sustained GPCR-Ca2+-signaling by α7 Rs, inhibiting constitutive endocytosis of α7 Rs. These observations underscore the role of α7 nAChR/G protein signaling and endocytic pathways in nic- upregulation of α7 Rs.

ISBN: 9798644902217Subjects--Topical Terms:

3172791
Cellular biology.
Subjects--Index Terms:

Acetylcholine

Signaling Mechanisms Underlying Nicotine-Induced Upregulation of α7 Nicotinic Acetylcholine Receptor (nAChR).
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245 1 0 $a Signaling Mechanisms Underlying Nicotine-Induced Upregulation of α7 Nicotinic Acetylcholine Receptor (nAChR).
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300 $a 262 p.
500 $a Source: Dissertations Abstracts International, Volume: 81-11, Section: B.
500 $a Advisor: Farley, Joseph.
502 $a Thesis (Ph.D.)--Indiana University, 2020.
506 $a This item must not be sold to any third party vendors.
520 $a α7 nicotinic acetylcholine receptors (nAChRs) are the second most abundant nAChR in brain and have been implicated to play a role in nicotine addiction. Though upregulation of α7 nAChRs by nicotine (Nic) has been demonstrated previously, particularly in in vivo studies, the cellular and molecular mechanisms responsible for nic-upregulation are poorly understood. We have shown ~2-fold functional and numerical upregulation of α7 nAChRs in Xenopus oocytes following nicotine treatment. Previously, we found that the nic-upregulation of α7 nAChR was dependent upon intracellular calcium [Ca2+]i. These observations raise critical questions as to: 1) the source of the obligatory [Ca2+]i increases, and 2) the downstream cellular processes responsible for nic-upregulation. This dissertation addresses those issues, using a combination of genetic, pharmacological, protein chemistry, and electrophysiological/biophysical approaches. In various cell types, G-protein signaling regulates α7 nAChR function via modulation of [Ca2+]i. α7 nAChR subunits, in their transmembrane (TM3-TM4) cytosolic loop, contain a canonical G- protein binding cluster (GPBC). Here, we demonstrate a role for α7 nAChR/Gαq protein interaction in the activation of a PLC-β pathway leading to prolonged increases in [Ca2+]i that, ultimately, inhibits constitutive endocytic pathways to cause nic-upregulation of α7 nAChRs. Mutation at GPBC or inhibition of endogenous Gαq expression abrogated nic-upregulation of α7 Rs. Furthermore, when Gαq was exogenously co-expressed with α7 Rs, we saw ~2X upregulation. But when a dominant negative Gαq was co-expressed with α7, a significant attenuation of nic-upregulation of wt α7 Rs was observed. We also found that the calcineurin inhibitor cyclosporine A produced 2X-upregulation of wt α7 Rs and occluded nic-upregulation. Endocytic-inhibitors produced ~2X upregulation of both wt (and mutant) α7 Rs and occluded nic-upregulation. Brefeldin A (BFA) failed to affect nic-upregulation. Serine-threonine kinase and tyrosine kinase-phosphorylation events have generally inhibitory effects on forward trafficking of α7 Rs. Nic-upregulation was unaffected when serine-365 or tyrosine-442 was mutated, further supporting the hypothesis that nic-upregulation of α7 arises from sustained GPCR-Ca2+-signaling by α7 Rs, inhibiting constitutive endocytosis of α7 Rs. These observations underscore the role of α7 nAChR/G protein signaling and endocytic pathways in nic- upregulation of α7 Rs.
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