This is a resubmission of a competing renewal to continue study of the nicotinic acetylcholine receptor (nAChR) gene family in human tissues of smokers and non-smokers. The principal site for biological action in tobacco use is thought to be the nicotinic acetylcholine receptors (nAChR). Expression of this complex gene family is known to be related in humans by smoking. nAChR are localized in both brain and in the periphery where they may have different functions. During the last funding period there were several major findings. 1) High affinity nicotinic receptors are up-regulated in human brain and peripheral blood cells of smokers. Receptor numbers in brain are directly correlated with the number of cigarettes smoked per day. 2) We have discovered that the human low affinity alpha-7 nAChR gene is partially duplicated, and is expressed as mRNA in both human brain and in peripheral blood cells. In data obtained since the continuing renewal was submitted, we have 4) [sic] characterized the nicotinic receptor subunit mRNA composition in primary human lymphocytes and polymorphonuclear cells (PMN), 5) shown that high affinity (nM) nicotine binding is regulated in the PMN of smokers in a dose dependent manner, and 6) confirmed a very high affinity (VHA, pM) nicotine binding activity in blood cells of smokers. The critiques of the reviewers are reflected in the modified proposal. We now propose 1) To determine the function of the expressed human alpha-7 nicotinic receptor gene duplication (dup-alpha-7), 2) To examine the regional expression and function of the very high affinity nicotine binding activity in human tissues, 3) To determine the contribution of mRNA for the full-length alpha-7 gene, the dup-alpha-7 gene and subunits expressed in peripheral blood cells where the VHA binding is found, to the smoking habit.
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