Pharmacology and Regulation of Nicotinic Receptor Subtypes

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Our objectives are to assess the pharmacology and regulation of the diverse heteromeric neuronal nicotinic cholinergic receptor (nAChR) subtypes in the mammalian CNS and autonomic nervous system. 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 CMS 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 CMS 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, a and ft. 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 a4/?2 subtype predominate in most areas of the CNS; whereas, the a3/?4 subtype provides the main template for two important autonomic ganglia: the sympathetic superior cervical ganglia and the parasympathetic nodose ganglia. The specific aims of the studies described in this proposal are: 1) To quantify the a402a5 subtype in brain areas and determine the influence of the a5 subunit on the regulation of these receptors by nicotine; 2) To identify, quantify and characterize the several different nAChR subtypes in the superior cervical ganglia and the nodose ganglia and to determine which of the different receptor subtypes are transported to the axon terminals of these ganglion neurons; 3) To study the subunit composition, pharmacology and regulation of nAChRs containing a6 subunits; and 4) To use a powerful new method 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 up-regulates CNS nAChRs.