Potential implications of human alpha7 nicotinic acetylcholine receptor genetic variants to the pathogenesis and treatment of HIV‐associated neurocognitive disorders

Abstract

The α7 nicotinic acetylcholine receptor (nAChR), a ligand gated ion channel characterized by its high calcium permeability, was shown to be upregulated in SH‐SY5Y cells exposed to HIV‐1 glycoprotein gp120 leading to Ca2+ overloading and cell death. These results suggest that HIV‐associated neurocognitive disorders (HAND) could be related to increased neuronal death as result of excessive Ca2+ influx through the upregulated α7 nAChR. Furthermore, these results also suggest that α7 nAChR antagonists can be exploited for neuroprotection in HIV‐1 seropositive patients. Genetic variants of the CHRNA7 gene (encodes α7 nAChR) that result in ion channels with increased expression and/or functionality could thus underlie increased risk of HAND. In addition, CHRNA7 genetic variants could also result in receptors with diminished response to antagonists. The hypothesis is that non‐synonymous single nucleotide polymorphisms (SNPs) located in the CHRNA7 gene could result in α7 nAChRs with enhanced functionality and/or expression levels, and with altered responses to drugs aimed at interfering with the excessive Ca2+ flow. Bupropion was studied as a model α7 nAChR antagonist. Herein we present data demonstrating that genetic variants of the CHRNA7 gene may result in α7 nAChRs with altered functionality and response to bupropion. Supported by NIMH grant # P30MH075673–07 and NIMHD grant # 8U54MD007587–03.