SUBUNIT SPECIFIC REGULATION OF NICOTINIC RECEPTORS

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DESCRIPTION (Applicant's Abstract): Why neuronal nicotinic receptors (nAChRs) comprise such a structurally diverse group of ligand-gated ion channels is unknown. However, it likely reflects their diverse roles in both the modulation and mediation o synaptic transmission throughout the nervous system. nAChRs have been implicated in learning and memory, chronic addiction and neurodegenerative diseases - all of which will be influenced by factors which regulate nAChR function. Thus, a greater understanding of the participation of particular nAChRs in these processe could be achieved by determining the link between the subtype of nicotinic acetylcholine receptor (nAChR) and its short and long-term regrulation. Within the framework of addiction, this proposal addresses the relationship between subunit composition of nAChRs and their function. The specific aims will be directed towards although not limited to, answering the question: Is nAChR desensitization both necessary and sufficient to explain the alterations in nAChR number and function observed following chronic exposure to nicotine? This aim will be pursued by examining nAChRs of known subunit composition in various expression systems. The study will focus on the interaction of nicotine, at tobacco-related concentrations, with nAChR subtypes the have properties consistent with their presence in the central nervous system (CNS). It will provide evidence for the following three hypotheses: (1) The functional properties of nAChRs can be predicted from thei subunit composition. The activation and desensitization characteristics of nAChRs will be examined with the idea that certain subunits will confer dominant properties upon receptors. (2) Biochemical regulation o receptor properties occurs in a nAChR subtype-specific manner. Individual subunits will be differentially amenable to regulation by other cellular factors (e.g., Ca2+ and phosphorylation). (3) The outcome o prolonged exposure of nAChRs to nicotine will be related to the functional propeffies and the biochemical state of particular nAChRs. A full understanding of the subunit-specific properties of nAChRs will predict how different nAChRs in the CNS should be affected under conditions of long-term exposure to tobacco-related concentrations of nicotine. Such data will suggest which types of receptors are likely to be important in the addiction process. In addition to addressing issues related to the neurobiology of addiction, these studies will provide further insights into the subunit composition and regulation of nAChRs in the CNS. Overall, this knowledge will be important, not only for the design of selective and potentially therapeutic agents, but also for understanding why a single class of receptors should have such a diverse molecular basis.