title: Sigma-1 receptor alters the kinetics of Kv1.3 voltage gated potassium channels but not the sensitivity to receptor ligands.
abstract: Sigma1 receptors (Sigma1R) are intracellular chaperone proteins that bind psychotropic drugs and also clinically used drugs such as ketamine and haloperidol. Co-expression of the Sigma1R has been reported to enhance the sensitivity of several voltage-gated ion channels to Sigma1R ligands. Kv1.3 is the predominant voltage-gated potassium channel expressed in T lymphocytes with a documented role in immune activation. To gain a better understanding of Sigma1R modulation of Kv ion channels, we investigated the effects of Sigma1R co-expression on Kv1.3 physiology and pharmacology in ion channels expressed in Xenopus oocytes. We also explored the protein domains of Kv1.3 necessary for protein:protein interaction between Kv1.3 and Sigma1R through co-immunoprecipitation studies. Slowly inactivating outward-going currents consistent with Kv1.3 expression were elicited on step depolarizations. The current characterized by E(rev), V(1/2), and slope factor remained unchanged when co-expressed with Sigma1R. Analysis of inactivation time constant revealed a faster Kv1.3 current decay when co-expressed with Sigma1R. However the sensitivity to Sigma1R ligands remained unaltered when co-expressed with the Sigma1R in contrast to the previously reported modulation of ligand sensitivity in closely related Kv1.4 and Kv1.5 voltage gated potassium channels. Co-immunoprecipitation assays of various Kv1.3 truncation constructs indicated that the transmembrane domain of the Kv1.3 protein was responsible for the protein:protein interaction with the Sigma1R. Sigma1R likely interacts with different domains of Kv ion channel family proteins resulting in distinct modulation of different channels.
authors.affiliation: Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA. mkinoshita@wisc.edu
authors.forename: Maho
authors.initials: M
authors.lastname: Kinoshita
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Matsuoka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Jennifer
authors.initials: J
authors.lastname: Mirrielees
authors.forename: Jay
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D051664:Kv1.3 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D051665:Kv1.4 Potassium Channel / Q000235:genetics / Q000378:metabolism; D051666:Kv1.5 Potassium Channel / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D017480:Receptors, sigma / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus
chemical_list: D051664:Kv1.3 Potassium Channel; D051665:Kv1.4 Potassium Channel; D051666:Kv1.5 Potassium Channel; D008024:Ligands; D017480:Receptors, sigma