My general research interest is in the modulation of receptor properties by neurotransmitters and drugs. Currently we are studying the mechanisms of modulation of the nicotinic cholinergic receptor by its neurotransmitter acetylcholine and by the neuropeptide substance P. Nicotinic receptor responsiveness is regulated by acetylcholine and other cholinergic agonists via desensitization. In fact there are several desensitization processes each of which occurs on a different time scale, ranging from milliseconds to several minutes. Nicotinic receptor responsiveness also appears to be regulated physiologically by substance P, an eleven amino acid peptide that inhibits nicotinic receptor activation.
P seems to be mediated by an increase in the rate and extent of desensitization.
We are studying the molecular bases of these mechanisms using several approaches and techniques. Nicotinic receptor-enriched purified electroplaque membranes have been used to study these processes on a more molecular level using various binding assays and a sodium ion flux assay. Recently we have begun to apply molecular biological methods to determine the structural determinants of agonist-induced desensitization and substance P inhibition, characterizing the properties of various combinations of wild type, chimeric, and mutated neuronal receptor subunits expressed in Xenopus oocytes. From these studies we have shown that substance P noncompetitively inhibits both neuronal and muscle type nicotinic receptors at submicromolar concentrations. This inhibition appears to be mediated by a direct interaction of the peptide with the receptor at a unique binding site which is distinct from the agonist, neurotoxin, or high affinity local anesthetic binding sites.