Potential Independent Action of Sigma Receptor Ligands Through Inhibition of the Kv2.1 Channel

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 Sep 24

PMID 28938641

Citations 11

Authors

Xinying Liu

Yingmei Fu

Huan Yang

Timur Mavlyutov

Jun Li

Christopher R McCurdy

Lian-Wang Guo

Bikash R Pattnaik

Affiliations

Soon will be listed here.

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.

Citing Articles

Cycling matters: Sex hormone regulation of vascular potassium channels.

Baldwin S, Jepps T, Greenwood I Channels (Austin). 2023; 17(1):2217637.

PMID: 37243715 PMC: 10228406. DOI: 10.1080/19336950.2023.2217637.

Retinoschisin and novel Na/K-ATPase interaction partners Kv2.1 and Kv8.2 define a growing protein complex at the inner segments of mammalian photoreceptors.

Schmid V, Wurzel A, Wetzel C, Plossl K, Bruckmann A, Luckner P Cell Mol Life Sci. 2022; 79(8):448.

PMID: 35876901 PMC: 9314279. DOI: 10.1007/s00018-022-04409-9.

The AMIGO1 adhesion protein activates Kv2.1 voltage sensors.

Sepela R, Stewart R, Valencia L, Thapa P, Wang Z, Cohen B Biophys J. 2022; 121(8):1395-1416.

PMID: 35314141 PMC: 9072587. DOI: 10.1016/j.bpj.2022.03.020.

SARS-CoV2 Infection and the Importance of Potassium Balance.

Causton H Front Med (Lausanne). 2021; 8:744697.

PMID: 34778307 PMC: 8578622. DOI: 10.3389/fmed.2021.744697.

Sigmar1's Molecular, Cellular, and Biological Functions in Regulating Cellular Pathophysiology.

Aishwarya R, Abdullah C, Morshed M, Remex N, Bhuiyan M Front Physiol. 2021; 12:705575.

PMID: 34305655 PMC: 8293995. DOI: 10.3389/fphys.2021.705575.

References

Maurice T, Su T . The pharmacology of sigma-1 receptors. Pharmacol Ther. 2009; 124(2):195-206. PMC: 2785038. DOI: 10.1016/j.pharmthera.2009.07.001. View

Holter P, Kunst S, Wolloscheck T, Kelleher D, Sticht C, Wolfrum U . The retinal clock drives the expression of Kcnv2, a channel essential for visual function and cone survival. Invest Ophthalmol Vis Sci. 2012; 53(11):6947-54. DOI: 10.1167/iovs.12-10234. View

Tchedre K, Huang R, Dibas A, Krishnamoorthy R, Dillon G, Yorio T . Sigma-1 receptor regulation of voltage-gated calcium channels involves a direct interaction. Invest Ophthalmol Vis Sci. 2008; 49(11):4993-5002. DOI: 10.1167/iovs.08-1867. View

Xu J, Zeng C, Chu W, Pan F, Rothfuss J, Zhang F . Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site. Nat Commun. 2011; 2:380. PMC: 3624020. DOI: 10.1038/ncomms1386. View

Mach R, Wu L, West T, Whirrett B, Childers S . The analgesic tropane analogue (+/-)-SM 21 has a high affinity for sigma2 receptors. Life Sci. 1999; 64(10):PL131-7. DOI: 10.1016/s0024-3205(99)00014-4. View

Mavlyutov T, Epstein M, Guo L . Subcellular localization of the sigma-1 receptor in retinal neurons - an electron microscopy study. Sci Rep. 2015; 5:10689. PMC: 4649997. DOI: 10.1038/srep10689. View

Brent P, Saunders H, Dunkley P . Intrasynaptosomal free calcium levels in rat forebrain synaptosomes: modulation by sigma (sigma) receptor ligands. Neurosci Lett. 1996; 211(2):138-42. DOI: 10.1016/0304-3940(96)12711-7. View

Czirjak G, Toth Z, Enyedi P . Characterization of the heteromeric potassium channel formed by kv2.1 and the retinal subunit kv8.2 in Xenopus oocytes. J Neurophysiol. 2007; 98(3):1213-22. DOI: 10.1152/jn.00493.2007. View

Wulff H, Castle N, Pardo L . Voltage-gated potassium channels as therapeutic targets. Nat Rev Drug Discov. 2009; 8(12):982-1001. PMC: 2790170. DOI: 10.1038/nrd2983. View

10.

Chu U, Mavlyutov T, Chu M, Yang H, Schulman A, Mesangeau C . The Sigma-2 Receptor and Progesterone Receptor Membrane Component 1 are Different Binding Sites Derived From Independent Genes. EBioMedicine. 2016; 2(11):1806-13. PMC: 4740303. DOI: 10.1016/j.ebiom.2015.10.017. View

11.

He Y, Zhang C, Gao X, Yao J, Hu C, Mei Y . Cyproheptadine enhances the I(K) of mouse cortical neurons through sigma-1 receptor-mediated intracellular signal pathway. PLoS One. 2012; 7(7):e41303. PMC: 3402501. DOI: 10.1371/journal.pone.0041303. View

12.

Mavlyutov T, Guo L . Peeking into Sigma-1 Receptor Functions Through the Retina. Adv Exp Med Biol. 2017; 964:285-297. PMC: 6283661. DOI: 10.1007/978-3-319-50174-1_19. View

13.

Wang J, Saul A, Roon P, Smith S . Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration. Proc Natl Acad Sci U S A. 2016; 113(26):E3764-72. PMC: 4932934. DOI: 10.1073/pnas.1521749113. View

14.

Hayashi T, Su T . Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell. 2007; 131(3):596-610. DOI: 10.1016/j.cell.2007.08.036. View

15.

Mavlyutov T, Nickells R, Guo L . Accelerated retinal ganglion cell death in mice deficient in the Sigma-1 receptor. Mol Vis. 2011; 17:1034-43. PMC: 3084245. View

16.

Kinoshita M, Matsuoka Y, Suzuki T, Mirrielees J, Yang J . Sigma-1 receptor alters the kinetics of Kv1.3 voltage gated potassium channels but not the sensitivity to receptor ligands. Brain Res. 2012; 1452:1-9. PMC: 3670091. DOI: 10.1016/j.brainres.2012.02.070. View

17.

Kourrich S, Su T, Fujimoto M, Bonci A . The sigma-1 receptor: roles in neuronal plasticity and disease. Trends Neurosci. 2012; 35(12):762-71. PMC: 3587126. DOI: 10.1016/j.tins.2012.09.007. View

18.

OConnell K, Loftus R, Tamkun M . Localization-dependent activity of the Kv2.1 delayed-rectifier K+ channel. Proc Natl Acad Sci U S A. 2010; 107(27):12351-6. PMC: 2901471. DOI: 10.1073/pnas.1003028107. View

19.

Su T, Wu X, Cone E, Shukla K, Gund T, Dodge A . Sigma compounds derived from phencyclidine: identification of PRE-084, a new, selective sigma ligand. J Pharmacol Exp Ther. 1991; 259(2):543-50. View

20.

Klumpp D, Song E, Pinto L . Identification and localization of K+ channels in the mouse retina. Vis Neurosci. 1995; 12(6):1177-90. DOI: 10.1017/s0952523800006805. View