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Inhibition of CaV2.3 channels by NK1 receptors is sensitive to membrane cholesterol but insensitive to caveolin-1

  • Ion channels, receptors and transporters
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Abstract

Voltage-gated, CaV2.3 calcium channels and neurokinin-1 (NK1) receptors are both present in nuclei of the central nervous system. When transiently coexpressed in human embryonic kidney (HEK) 293 cells, CaV2.3 is primarily inhibited during strong, agonist-dependent activation of NK1 receptors. NK1 receptors localize to plasma membrane rafts, and their modulation by Gq/11 protein-coupled signaling is sensitive to plasma membrane cholesterol. Here, we show that inhibition of CaV2.3 by NK1 receptors is attenuated following methyl-β-cyclodextrin (MBCD)-mediated depletion of membrane cholesterol. By contrast, inhibition of CaV2.3 was unaffected by intracellular diffusion of caveolin-1 scaffolding peptide or by overexpression of caveolin-1. Interestingly, MΒCD treatment had no effect on the macroscopic biophysical properties of CaV2.3, though it significantly decreased whole-cell membrane capacitance. Our data indicate that (1) cholesterol supports at least one component of the NK1 receptor-linked signaling pathway that inhibits CaV2.3 and (2) caveolin-1 is dispensable within this pathway. Our findings suggest that NK1 receptors reside within non-caveolar membrane rafts and that CaV2.3 resides nearby but outside the rafts. Raft-dependent modulation of CaV2.3 could be important in the physiological and pathophysiological processes in which these channels participate, including neuronal excitability, synaptic plasticity, epilepsy, and chronic pain.

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Acknowledgments

We thank Dr. Caroline Dart (University of Liverpool, Liverpool, UK) for sharing the rat caveolin-1 expression plasmid. We thank Dr. Brett Adams (Utah State University, Logan, UT, USA) and Dr. Roger A. Bannister (University of Colorado Denver-AMC, Aurora, CO, USA) for helpful comments on the manuscript. We thank Nohelia Meza-Meza for helpful suggestions on the manuscript. This work was supported by grants from CONACyT (169006 to U.M.; 155035 to S.S-A; 157245 to A.A.R-M) and the Universidad Autónoma de San Luis Potosí (C13-FRC-01-03.03 to U.M.; C-12-FRC-09-12.12 to S.S-A.; C12-FRC-09-19.19 to A.A.R-M.).

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The authors declare that they have no conflict of interest.

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  1. Department of Physiology and Biophysics, College of Medicine, Universidad Autónoma de San Luis Potosí, Carranza #2405, San Luis Potosí, SLP, 78210, México

    Yamhilette Licon, Deniss Leandro, Catalina Romero-Mendez, Aldo A. Rodriguez-Menchaca, Sergio Sanchez-Armass & Ulises Meza

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  1. Yamhilette Licon
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  2. Deniss Leandro
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  3. Catalina Romero-Mendez
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Correspondence to Ulises Meza.

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Licon, Y., Leandro, D., Romero-Mendez, C. et al. Inhibition of CaV2.3 channels by NK1 receptors is sensitive to membrane cholesterol but insensitive to caveolin-1. Pflugers Arch - Eur J Physiol 467, 1699–1709 (2015). https://doi.org/10.1007/s00424-014-1605-0

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