The nicotinic receptor alpha5 coding polymorphism rs16969968 as a major target in disease: Functional dissection and remaining challenges

Abstract

Nicotinic acetylcholine receptors (nAChRs) are major signalling molecules in the central and peripheral nervous system. Over the last decade, they have been linked to a number of major human psychiatric and neurological conditions, like smoking, schizophrenia, Alzheimer's disease and many others. Human Genome-Wide Association Studies (GWAS) have robustly identified genetic alterations at a locus of chromosome 15q to several of these diseases. In this review, we discuss a major coding polymorphism in the alpha5 subunit, referred to as α5SNP, and its functional dissection in vitro and in vivo. Its presence at high frequency in many human populations lends itself to pharmaceutical intervention in the context of 'positive allosteric modulators' (PAMs). We will present the prospects of this novel treatment, and the remaining challenges to identify suitable molecules.

Keywords: Genome-wide Association Studies; drug discovery; human genetics; nicotine addiction; nicotinic acetylcholine receptor; positive allosteric modulator; schizophrenia; single nucleotide polymorphism.