Potential independent action of sigma receptor ligands through inhibition of the Kv2.1 channel.

Bikash Pattnaik // Publications // Aug 29 2017

PubMed ID: 28938641

Author(s): Liu X, Fu Y, Yang H, Mavlyutov T, Li J, McCurdy CR, Guo LW, Pattnaik BR. Potential independent action of sigma receptor ligands through inhibition of the Kv2.1 channel. Oncotarget. 2017 Jul 26;8(35):59345-59358. doi: 10.18632/oncotarget.19581. eCollection 2017 Aug 29. PMID 28938641

Journal: Oncotarget, Volume 8, Issue 35, Aug 2017

The sigma-1 receptor (σ1-R) and sigma-2 receptor (σ2-R) are potential drug targets for treatment of cancer, pain, depression, retinal degeneration and other neuronal diseases. Previous reports show that sigma-1 receptor modulates the activities of multiple channels. We are interested in possible sigma receptor modulation of Kv2.1, a K+ channel abundant in retinal photoreceptors. We tested the effect of established sigma receptor ligands on Kv2.1 channels which were stably expressed in HEK293 cells. Surprisingly, σ1-R antagonists inhibited Kv2.1 currents in both wild type and σ1-R knockout HEK293 cells that we engineered using the CRISPR/Cas9 technology. Moreover, PB28, a σ1-R antagonist and also σ2-R agonist, inhibited Kv2.1 in σ1-R knockout cells, but this action was not blocked by the σ2-R antagonists that did not have an effect on Kv2.1. We also observed inhibition of electroretinogram by PB28 in wild type as well as σ1-R knockout mice. Thus, the results in this study indicate that the Kv2.1-inhibiting function of the sigma ligands is not sigma receptor dependent, suggesting a direct effect of these ligands on the Kv2.1 channel.