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J Biol Chem. April 20, 2012; 287 (17): 14259-69.

Modulation of gain-of-function α6*-nicotinic acetylcholine receptor by β3 subunits.

Dash B , Lukas RJ .

We previously have shown that β3 subunits either eliminate (e.g. for all-human (h) or all-mouse (m) α6β4β3-nAChR) or potentiate (e.g. for hybrid mα6hβ4hβ3- or mα6mβ4hβ3-nAChR containing subunits from different species) function of α6*-nAChR expressed in Xenopus oocytes, and that nAChR hα6 subunit residues Asn-143 and Met-145 in N-terminal domain loop E are important for dominant-negative effects of nAChR hβ3 subunits on hα6*-nAChR function. Here, we tested the hypothesis that these effects of β3 subunits would be preserved even if nAChR α6 subunits harbored gain-of-function, leucine- or valine-to-serine mutations at 9'' or 13'' positions (L9''S or V13''S) in their second transmembrane domains, yielding receptors with heightened functional activity and more amenable to assessment of effects of β3 subunit incorporation. However, coexpression with β3 subunits potentiates rather than suppresses function of all-human, all-mouse, or hybrid α6((L9''S or V13''S))β4*- or α6(N143D+M145V)(L9''S)β2*-nAChR. This contrasts with the lack of consistent function when α6((L9''S or V13''S)) and β2 subunits are expressed alone or in the presence of wild-type β3 subunits. These results provide evidence that gain-of-function hα6hβ2*-nAChR (i.e. hα6(N143D+M145V)(L9''S)hβ2hβ3 nAChR) could be produced in vitro. These studies also indicate that nAChR β3 subunits can be assembly partners in functional α6*-nAChR and that 9'' or 13'' mutations in the nAChR α6 subunit second transmembrane domain can act as gain-of-function and/or reporter mutations. Moreover, our findings suggest that β3 subunit coexpression promotes function of α6*-nAChR.

PubMed ID: 22315221
PMC ID: PMC3340145
Article link: J Biol Chem.
Grant support: DA015389 NIDA NIH HHS , Intramural NIH HHS, R01 DA015389 NIDA NIH HHS

External Resources:

Booker, 2007, Pubmed[+]

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