51²è¹Ýapp

We study the molecular pharmacology of neuronal nicotinic acetylcholine receptors (nAChRs). These ligand-gated ion channels are the seat of nicotine addiction and are implicated in a wide range of other neurological abnormalities such as Parkinson’s disease and attention disorders. Most recently, we have been interested in the positive allosteric modulation of nAChRs, the phenomenon of a drug enhancing the activity an agonist such as acetylcholine from a remote, distinct site on the receptor protein. Allosteric modulation of nAChRs is growing in importance as it becomes better understood and as novel compounds with this pharmacological profile are identified. We elucidated the mechanism of action for the compound morantel and we determined that morantel binds at subunit interfaces distinct from those that bind agonist. As an extension of these findings, we are currently working to identify the molecular determinants through which the modulator binding site communicates with the agonist binding site and with the channel gate directly, and to identify the molecular determinants of morantel site specificity. These studies employ macroscopic voltage-clamp recordings combined with mutational and chemical modification analyses. To support these primary aims, we are also exploring the potentiation mechanism by single-channel recordings and mathematical modeling. Our work is innovative because we are challenging the paradigm of activation of nAChRs by occupying two agonist binding sites: We are studying a previously unknown nAChR ligand binding site, and our work stands to substantially strengthen the foundation for rational design of nAChR positive allosteric modulators, a drug class with possible clinical applications.