Isoform-Specific Mechanisms Of A3β4ˆ—-Nicotinic Acetylcholine Receptor Modulation By The Prototoxin Lynx1

Department

neurobiology

Document Type

Article

Abstract

This study investigates - for the first time to our knowledge - the existence and mechanisms of functional interactions between the endogenous mammalian prototoxin, lynx1, and α3- and β4-subunit-containing human nicotinic acetylcholine receptors (α3β4∗-nAChRs). Concatenated gene constructs were used to express precisely defined α3β4∗-nAChR isoforms (α3β4)2β4-, (α3β4)2α3-, (α3β4)2α5(398D)-, and (α3β4)2a5(398N)-nAChR in Xenopus oocytes. In the presence or absence of lynx1, α3β4∗-nAChR agonist responses were recorded by using 2-electrode voltage clamp and single-channel electrophysiology, whereas radioimmunolabeling measured cellsurface expression. Lynx1 reduced (α3β4)2β4-nAChR function principally by lowering cell-surface expression, whereas single-channel effects were primarily responsible for reducing (α3β4)2α3-nAChR function [decreased unitary conductance (‡50%), altered burst proportions (3-fold reduction in the proportion of long bursts), and enhanced closed dwell times (3- to 6-fold increase)]. Alterations in both cell-surface expression and single-channel properties accounted for the reduction in (α3β4)2α5-nAChR function that wasmediated by lynx1. No effects were observed when a3b4∗-nAChRs were coexpressed with mutated lynx1 (control). Lynx1 is expressed in the habenulopeduncular tract, where α3β4∗-α5∗-nAChR subtypes are critical contributors to the balance between nicotine aversion and reward. This gives our findings a high likelihood of physiologic significance. The exquisite isoform selectivity of lynx1 interactions provides new insights into the mechanisms and allosteric sites [α(2)-interface containing] by which prototoxins canmodulatenAChRfunction. - George, A. A., Bloy, A.,Miwa, J. M., Lindstrom, J. M., Lukas, R. J., Whiteaker, P. Isoform-specific mechanisms of α3β4∗-nicotinic acetylcholine receptor modulation by the prototoxin lynx1.

Publication Date

4-1-2017

Publication Title

FASEB Journal

ISSN

08926638

Volume

31

Issue

4

First Page

1398

Last Page

1420

Digital Object Identifier (DOI)

10.1096/fj.201600733R

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