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THE COUNCIL FOR TOBACCO REBEARCH-U.S.A., INC. SUPPORTING BIOMEDIC4L INVESTIGATION Menorandum To: Dr. H. McAllister and Staff Fran: D.H.Ford Re: Site visit with Dr. Lorna Role, Columbia University, College of Physicians and Surgecns, July 14, 1993. Grant No. 2782A entitled "Ma3ulaticaz of Central Nicotine-Receptor Channels" Site visitors: A. Eisenberg and D. Ford Aim: To determine if different subtypes of nicotine activated channels (nACh receptors) expressed by CNS neurons differ in their modulatial by peptides and secrnd messengers. Further, does activation of central nACh receptors modulate the respcne of other reeeptcrs or the release of ncn-chclinergic or cholinergic transmitters? Results: Fran her previously supported CTR program Dr. Role has determi.ned that nicotine activated receptors in the PNS are modulated by both protein kinase A and C. She further demonstrated by use of patch clamp techniques that there are four subtypes of nACh receptors expressed in neurons of the habenula nucleus (Neurens involved in scme autonar~i.c funct.icns as well as in arcusal). Her cbservaticns have revealed that the S, M and XL subtypes of these receptors in these neurons are differently modulated by PKA. Inasmuch as there are seven types of alpha peptides and four types of beta peptides which can be used in assembling nFL:h receptors in the CNS, it is no surprise to ccnclude that there may be over 5000 variants and that it has already been repartsd that acti.vaticn of the nPCh receptor regulates Na, Ca, K and C1 channels. What is even more interesting, as shown by Role's recent data is that the type of receptor on a neurrn varies with its location, being different cn dendrites, sana and axcnal terminal. Scme of her early data suggests that the nicotinic gated Ca channels are very important in maintaining neurcnal functi.cn. Hc,wever, as we discussed, it is well kncan that excessive intraoellular Ca can lead to cell death and may actually be involved in programed cell death. What is beginning to appear likely is that the wide diversity of nACh receptcrs, with different types at different locations in a neuron and with different types regirnally located in ccnjuncticn with what appear to be differing mo3ulations in resprnse to the neuropeptides provide for a considerable degree of plasticity in respcnse. Camnent: An extremely interesting progra¢n in which Dr. Rols is making excellent progress. There appear to be many ways in which the infcrmaticn she is obtaining relates to behaviour, learning and a variety of neurological disorders. If, as many researchersare Oinning to believe, many of these disorders such as Alzheimer's Disease, Parkinson's syndrane, Huntingtcn's Chorea may have a canncn etiology. Dr. Role's cbservaticaz thatactivaticn on the nACh reeeptor (one of it's subtypes) .,,n..~.h may open up Ca channels,,,in excess could lead to neuronal death. Cbvicusly, the details of how this might occur are still to be determined. Dr.Role is a very experienced investigator in neurobialogical research and well aquainted with the difficulties of the techniques she utilizes Her expertise in this field of endeavor was just recently recognized by her peers when she received the Jacb Javitts award. This is an exciting program which should provide continued understanding in not only the diversity of the nACh receptors, but on haa they are involved in a wide variety of neurcnal functims. DHF