Mysterious alpha6-containing nAChRs: function, pharmacology, and pathophysiology.

Neuronal nicotinic acetylcholine receptors (nAChRs) are the superfamily of ligand-gated ion channels and widely expressed throughout the central and peripheral nervous systems. nAChRs play crucial roles in modulating a wide range of higher cognitive functions by mediating presynaptic, postsynaptic, and extrasynaptic signaling. Thus far, nine alpha (alpha2-alpha10) and three beta (beta2, beta3, and beta4) subunits have been identified in the CNS, and these subunits assemble to form a diversity of functional nAChRs. Although alpha4beta2- and alpha7-nAChRs are the two major functional nAChR types in the CNS, alpha6*-nAChRs are abundantly expressed in the midbrain dopaminergic (DAergic) system, including mesocorticolimbic and nigrostriatal pathways, and particularly present in presynaptic nerve terminals. Recently, functional and pharmacological profiles of alpha6*-nAChRs have been assessed with the use of alpha6 subunit blockers such as alpha-conotoxin MII and PIA, and also by using alpha6 subunit knockout mice. By modulating DA release in the nucleus accumbens (NAc) and modulating GABA release onto DAergic neurons in the ventral tegmental area (VTA), alpha6*-nAChRs may play important roles in the mediation of nicotine reward and addiction. Furthermore, alpha6*-nAChRs in the nigrostriatal DAergic system may be promising targets for selective preventative treatment of Parkinson's disease (PD). Thus, alpha6*-nAChRs may hold promise for future clinical treatment of human disorders, such as nicotine addiction and PD. In this review, we mainly focus on the recent advances in the understanding of alpha6*-nAChR function, pharmacology and pathophysiology.