Modulation of recombinant, α2, α3 or α4-nicotinic acetylcholine receptor (nAChR) function by nAChR β3 subunits

J. Neurochem. (2012) 121, 349–361. The nicotinic acetylcholine receptor (nAChR) β3 subunit is thought to serve an accessory role in nAChR subtypes expressed in dopaminergic regions implicated in drug dependence and reward. When β3 subunits are expressed in excess, they have a dominant‐negative effect on function of selected nAChR subtypes. In this study, we show, in Xenopus oocytes expressing α2, α3 or α4 plus either β2 or β4 subunits, that in the presumed presence of similar amounts of each nAChR subunit, co‐expression with wild‐type β3 subunits generally (except for α3*‐nAChR) lowers amplitudes of agonist‐evoked, inward peak currents by 20–50% without having dramatic effects (≤ 2‐fold) on agonist potencies. By contrast, co‐expression with mutant β3V9’S subunits generally (except for α4β2*‐nAChR) increases agonist potencies, consistent with an expected gain‐of‐function effect. This most dramatically demonstrates formation of complexes containing three kinds of subunit. Moreover, for oocytes expressing nAChR containing any α subunit plus β4 and β3V9’S subunits, there is spontaneous channel opening sensitive to blockade by the open channel blocker, atropine. Collectively, the results indicate that β3 subunits integrate into all of the studied receptor assemblies and suggest that natural co‐expression with β3 subunits can influence levels of expression and agonist sensitivities of several nAChR subtypes. nAChR β3 subunits affects agonist sensitivity and efficacy; and rates of receptor desensitization to various degrees Natural incorporation of β3 subunits could occur into various nAChR subtypes. Such incorporation is shown to have modest effects on sensitivity to endogenous ACh or exogenous nicotine; a milder negative effect on levels of nAChR function, the exceptions being a larger negative effect on α3β2*‐ and α4β2‐*‐nAChR; and mostly an undistinguishable effect on rates of desensitization. These data could be relevant for developing therapeutics for treatment of nicotine addiction.