Functional characterization of human α7 nicotinic acetylcholine receptor genetic variants (1147.4)

Abstract

The α7 nicotinic acetylcholine receptor (nAChR) is a ligand‐gated ion channel that is abundantly expressed throughout the central nervous system (CNS) and has been linked to Alzheimer’s disease, Parkinson’s, and Schizophrenia. In addition, the α7 nAChR has been identified in non‐neuronal cells such as macrophages, where it plays an essential role in the control of inflammation through the cholinergic anti‐inflammatory pathway; and cancer cells, where its activation promotes tumor growth, angiogenesis, metastasis, and cancer stem cell proliferation. Consistent with its protagonistic role in various diseases, the α7 nAChR is extensively studied by the pharmaceutical industry. The CHRFAM7A gene, a partial duplication of the gene encoding the α7 nAChR (CHRNA7), encodes dupα7, which is a protein that was recently demonstrated to act as negative regulator of the α7 functionality. The objective of the research presented herein was to examine whether genetic variants of the CHRNA7 gene could result in α7 receptors with significant changes in functionality, expression, and proneness to dupα7 regulation. To achieve this objective, two‐electrode voltage clamp, cell‐attached patch clamp and confocal microscopy experiments were performed using Xenopus laevis oocytes as expression system. We found that genetic variants of the CHRNA7 gene can result in significant changes in functionality and expression of the α7 nAChR in addition to significantly affecting the capacity of dupα7 to negatively regulate α7. In conclusion, our results demonstrate that genetic variants of the CHRNA7 gene can modify the functionality, expression, and regulation of the α7 nAChR, and should thus be considered when designing drugs that target this important receptor.Grant Funding Source: Supported by NIMH grant # P30MH075673‐07 and NIMHD grant # 8U54MD007587‐03.