Tobacco Documents Online

THE COUNCIL FOR TOBACCO RESEARCH-U.S.A.. INC. !)UO TIIIKll ALVENUE NEW YORK. N.Y. 10022 Memorandum To: Dr. J.F.Glenn and Staff From: D.H. Ford Re: Site visit with Dr. Ronald-Lucas, Barrow Neurological Institute Phoenix, AZ, Feb. 14, 1990. Grant No. 1693AR2 entitled "Influence of nicotine on neuronal expression of acetylcholine receptors." Goals: To determine the degree to which the nACh receptor is hetero- geneous and whether or not heterogeneity varies with cell type. Further, does heterogeneity of receptor relate to differences;in second messenger systems. Results: The studies performed over the last 41,2 years have demonstrated that there are at least 5 kinds of nACh receptor, which vary according to cell type, as determined by agonist and antagonist binding studies. There are also nAChR-like high afficnity binding sites for toxins which do not appear to be nicotine-gated ion channels, but may be coupled to second messenger signaling.systems. Questions to be resolved in relation to the different receptor subtypes are the conditions under which each is activated. Do the different subtypes relate to differences in type of ion channel opened (Na, Cl, Ca or K)? If so, does the difference in ion channel relate to a different functional response? The nACh receptor appears to fatigue rapidly during continuous stimulation until it fails to function. Preliminary work suggests that some of these fatigued receptors may be internalized and degraded, to be replaced by newly synthesized receptors.(Would such receptors, still localized in the cytoplasm, account for the apparent presence of nicotine bound in the cytoplasm, as shown by Fuxe, Lindstrom and by Clarke?) Another area currently under investigation relates to the neuro- peptide thymosin which appears to have a role in formation of new ACh receptors as well as a role in the regulation of c-fos. The possible interaction of this association with thymosin may prove to be signifi- cant in the newly focussed interest in the interrelationship between the immune and neuroendocrine systeip, since both appear to be influenced by nicotine. A final series of ongoing studies deal with an attempt to determine.the gene sequences which determine which form of n.AChR is formed, what factors 3nfluence expression of these genes...are the differences in receptor subtype translational or post-translational? Comment: While Dr. Lukas is director of neurochemistry and cell . culture, he is currently also very active in the direction of this entire institute which encompasses a very complete multidisciplinary program in neurobiology. This includes a physiology component where a young investigator (Dr Craig) is utilizing a cat model to study pain stimulus transmission in the dorsomedial, ventroposterolateral, centro- median and intralaminar nuclei of the thalamus (provide for specific and non-specific transmission and recognition of pain). He has already used several ligands which alter the electrophysiologic response. He plans to try nicotine in the future, and if there is any 'interesting' response, he may approach CTR with a letter of inquiry. This continues to be an interesting program providing further illumin- ation of the complexities of thenACh receptor. DHF