Pharmacology and Regulation of Nicotinic Receptor Subtypes

Georgetown University, Washington DC

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Abstract

Our objectives are to assess the pharmacology and regulation of the diverse heteromeric neuronal nicotinic cholinergic receptor (nAChR) subtypes in the mammalian central nervous system (CNS). These receptors are widely distributed in the CNS, where they modulate release of several neurotransmitters in important neuronal pathways. Thus, they influence a wide range of functions, and they have been clearly implicated in nicotine addiction. In addition, these receptors are thought to play an important role in a wide range of other CNS disorders including Parkinson's disease, Alzheimer's disease, Tourette's syndrome and neuropathic pain. Nicotinic receptors are also crucial for normal functioning of the autonomic nervous system, and thus they influence virtually all organ systems in the body. These receptors are pentameric structures assembled from 11 subunits representing 2 classes, alpha and beta. The subunit composition of a receptor defines its subtype and determines its pharmacological and biophysical properties, which vary subtly, or not so subtly, among the particular subtypes. Two nAChR subtypes seem to form the main templates for several other heteromeric receptors found in the CNS and autonomic nervous systems. Receptors based on the alpha4beta2 subtype predominate in most areas of the CNS; whereas, the alpha3beta4 subtype provides the main template autonomic ganglia. The specific aims of the studies described in this proposal are: 1) To quantify the alpha4beta2alpha5 subtype in brain areas and determine the influence of the alpha5 subunit on the regulation of these receptors by nicotine; 2) To study the subunit composition, pharmacology and regulation of nAChRs containing alpha6 subunits; and 3) To use a powerful new method, expression of concatameric receptors consisting of all five subunits fused into a single defined receptor, to determine the properties of mixed heteromeric nAChRs of known subunit composition, stoichiometry, and subunit order. The studies described in this proposal will lead to a better understanding of important differences in the pharmacology and regulation among these different receptor subtypes and help us to understand how nicotine regulates CNS nAChRs.