| First Author | Sciaccaluga M | Year | 2015 |
| Journal | FASEB J | Volume | 29 |
| Issue | 8 | Pages | 3389-98 |
| PubMed ID | 25911614 | Mgi Jnum | J:225451 |
| Mgi Id | MGI:5693328 | Doi | 10.1096/fj.14-268102 |
| Citation | Sciaccaluga M, et al. (2015) Crucial role of nicotinic alpha5 subunit variants for Ca2+ fluxes in ventral midbrain neurons. FASEB J 29(8):3389-98 |
| abstractText | Neuronal nicotinic acetylcholine receptors (nAChRs) containing the alpha5 subunit modulate nicotine consumption, and the human CHRNA5 rs16969968 polymorphism, causing the replacement of the aspartic acid residue at position 398 with an asparagine (alpha5DN), has recently been associated with increased use of tobacco and higher incidence of lung cancer. We show that in ventral midbrain neurons, the alpha5 subunit is essential for heteromeric nAChR-induced intracellular-free Ca(2+) concentration elevations and that in alpha5(-/-) mice, a class of large-amplitude nicotine-evoked currents is lost. Furthermore, the expression of the alpha5DN subunit is not able to restore nicotinic responses, indicating a loss of function by this subunit in native neurons. To understand how alpha5DN impairs heteromeric nAChR functions, we coexpressed alpha4, alpha5, or alpha5DN subunits with a dimeric concatemer (beta2alpha4) in a heterologous system, to obtain nAChRs with fixed stoichiometry. Both alpha5(beta2alpha4)2 and alpha5DN(beta2alpha4)2 nAChRs yielded similar levels of functional expression and Ca(2+) permeability, measured as fractional Ca(2+) currents (8.2 +/- 0.7% and 8.0 +/- 1.9%, respectively), 2-fold higher than alpha4(beta2alpha4)2. Our results indicate that the loss of function of nicotinic responses observed in alpha5DN-expressing ventral midbrain neurons is neither due to an intrinsic inability of this subunit to form functional nAChRs nor to an altered Ca(2+) permeability but likely to intracellular modulation. |
