This FIRCA application represents a new direction of the Parent Grant which is entitled """"""""Modulation of Muscarinic Responses by Inositol Lipids"""""""". The focus of the proposed project is to test the hypotheses that: (a) pharmacological agents which modulate the conformation of muscarinic receptors in a positive allosteric manner are able to discriminate in their binding to various subtypes of these receptors; (b) such selectivity in binding is reflected in a preferential potentiation of the second messenger signals coupled to certain muscarinic receptor subtypes more than others. This pharmacological profile should result in fine-tuning of signal transduction mechanisms coupled to activation of muscarinic receptors in tissues endowed with the presence of multiple receptor subtypes. Alcuronium, which is a representative of this class of drugs, has been discovered in the laboratory of Dr. Tucek to increase the binding of certain ligands to muscarinic receptors in a manner which suggests that it interacts with the receptor at a distinct domain in relation to the binding site of conventional competitive muscarinic antagonists. This interaction results in a unique enhancement of the affinity of the latter class of ligands. Most other muscarinic allosteric modulators regulate the receptor conformation in a negative fashion. Alcuronium will be used in the proposed studies as a prototype compound. This project complements the long-standing interest of the P.I. in the mechanisms of allosteric regulation of muscarinic receptors. It also focuses on research questions which are closely related to the specific aims of the Parent Grant in terms of modulation of receptor function at the level of agonist-receptor interaction. The parallel goal of the Parent Grant is to explore the cross-talk between intracellular second messenger mechanisms which controls the responsiveness of muscarinic receptors.
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