Sigma Receptor Structure/Function/K+ Channel Modulation

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DESCRIPTION (provided by applicant): Sigma receptors are unique "non-opioid" receptors that are found in the mammalian central nervous system and peripheral organs. The function of the sigma receptor is unknown, but it is believed to mediate the immunosuppressant, antipsychotic, and neuroprotective effects of drugs, such as haloperidol, ditolylguanidine (DTG), pentazocine, and cocaine. Several observations indicate potential therapeutic uses of sigma ligands. Some atypical neuroleptics (e.g., haloperidol) have high affinity for the sigma receptor, which has led to the possibility of creating a new class of antipsychotic drugs, which are devoid of dopaminergic activity and can bind selectively to the sigma receptor. A genetic linkage has been reported for the sigma receptor and schizophrenia. Selective sigma ligands can block the behavioral and toxic functions of cocaine, and cocaine can also serve as a sigma ligand with reasonable affinity. These observations raise the possibility that the sigma receptor may be a target for the treatment of cocaine-related responses. The potent immunosuppressant SR31747A, which binds to the sigma receptor, exhibits immunosuppressive properties and antiproliferative activity in mouse and human T lymphocytes. These observations may explain the immunosuppressant properties of cocaine and other sigma ligands and lead to a new generation of immunosuppressants. A number of studies have shown that sigma receptor ligands modulate ion channels in the plasma membrane to regulate excitability. Target channels are general voltage-gated K+ channels, and the modulation entails an inhibition of the current elicited by positive voltage steps. The focus of this research proposal is to characterize the structure of the sigma1 receptor binding site and the manner by which the sigma1 receptor modulates K+ channels. Three areas of focus will be investigated: (1) synthesis and characterization of novel high affinity sigma receptor agonist and antagonist photo affinity labels; (2) mapping the ligand binding site(s) of the sigma1 receptor; and (3) determination of the properties of the sigma1 receptor interaction with Kvl.4 potassium channels and other protein partners. These experiments will be performed through the combined use of photoactivatable molecules, electrophysiology, and recombinant and fusion proteins.