The nicotinic acetylcholine receptor (nAChR) ?7 subtype has numerous properties that distinguish it from other nAChRs, including activation by both the neurotransmitter ACh and the ubiquitous tissue factor choline, a feature that may be associated with its important functional expression in both neuronal and non-neuronal cells, including cells of the immune system. Expressed in such diverse tissues, ?7 nAChR are also recognized as potentially important therapeutic targets for diverse indications including CNS disorders like Alzheimer's disease and schizophrenia, as well as peripheral disorders, especially inflammatory diseases and pain. Traditionally, study of ?7 and other nAChR has focused on ligands that activate or antagonize the receptor's ion channel; however, it has recently been shown that the best drugs for treating the peripheral disorders may be those that preferentially induce the alternative conformational states associated with ion channel desensitization. Consistent with the hypothesis that the selective targeting of ?7 receptors for peripheral disorders will require qualitatively different drugs from those for CNS disorders, cells which mediate ?7 control of inflammation do not have ?7 receptors with activatable ion channels, possibly due to the co-expression of other gene products that limit ion channel function and confer distinct pharmacological profiles for ?7 function in those cells. We have used electrophysiological and biochemical approaches to determine how the multiple conformational states of ?7 are selectively regulated by ligands and have used allosteric modulators to identify novel molecules we characterize as silent agonists. Our data indicate that silent agonists will be useful to selectively target ?7 receptors for peripheral diseases, while alternative ?7 - selectie agonists with ion channel efficacy may be better for CNS disorders. Drugs with selectivity for specific indications will be less likely to have crossover side effects when used therapeutically. In this project we will continue to refine and develop these concepts for selective targeting of ? receptors with silent agonists by testing hypotheses related to a novel pharmacophore(s) for such drugs and by further identifying elements in the ligand binding domain that differentially regulate the stabilization of specific conformational states, including those which are active for signal transduction in non-neuronal cells. We will test hypotheses related to accessory proteins that may differentially regulate ?7 function in different cell types. We will test our new ligands and previously identified reference compounds in cell- based assays for the regulation of cytokine production and mediators of signal transduction that are relevant to inflammatory disease and pain. We will also directly evaluate their efficacy in vivo for reducing pain from inflammation. These studies will allow us to test our core hypothesis that the therapeutic targeting of ?7 for specific indications will rely on identifying ligands that discriminate betwee channel-dependent and channel-independent signaling modes.
Two requirements for developing new medicines are identifying target molecules and understanding how the function of those molecules should be controlled to treat the disease. The ?7 type of nicotine receptor, which is found both in the brai and in white blood cells, is a target for several different types of disorders: in the brain, for treating Alzheimer's disease and schizophrenia; and in white blood cells, for treating arthritis, asthma, and sepsis. Our work shows that ?7 receptors function differently in white blood cells from how they work in the brain, and we are developing a new class of drugs that will be useful for inflammatory diseases with reduced likelihood of side-effects.
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