Potential independent action of sigma receptor ligands through inhibition of the Kv2.1 channel
| Autor: | Bikash R. Pattnaik, Lian-Wang Guo, Jun Li, Huan Yang, Yingmei Fu, Christopher R. McCurdy, Xinying Liu, Timur A. Mavlyutov |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Gerontology medicine.medical_specialty sigma receptor ligands business.industry Public health Sigma receptor electroretinogram patch-clamp Sigma ligands Independent action Kv2.1 channel 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology Retinal Photoreceptors Family medicine medicine business CRISPR/Cas9 030217 neurology & neurosurgery Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Xinying Liu 1, * , Yingmei Fu 2, 3, * , Huan Yang 2 , Timur Mavlyutov 2, 4 , Jun Li 2, 5 , Christopher R. McCurdy 6 , Lian-Wang Guo 2, 7, 8 and Bikash R. Pattnaik 7, 9 1 Departments of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA 2 Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA 3 Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China 4 Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA 5 Department of Ophthalmology, The Third People’s Hospital of Dalian, Dalian, PR China 6 Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA 7 McPherson Eye Research Institute, University of Wisconsin, Madison, WI, USA 8 Department of Surgery and Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA 9 Department of Pediatrics, Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA * These authors have contributed equally to this work Correspondence to: Bikash R. Pattnaik, email: bikashp@pediatrics.wisc.edu Lian-Wang Guo, email: Lianwang.Guo@osumc.edu Keywords: Kv2.1 channel, CRISPR/Cas9, sigma receptor ligands, patch-clamp, electroretinogram Received: April 21, 2017 Accepted: June 16, 2017 Published: July 26, 2017 ABSTRACT 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. |
| Databáze: | OpenAIRE |
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