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σ-1 Receptor Inhibition of ASIC1a Channels is Dependent on a Pertussis Toxin-Sensitive G-Protein and an AKAP150/Calcineurin Complex

Abstract

ASIC1a channels play a major role in various pathophysiological conditions including depression, anxiety, epilepsy, and neurodegeneration following ischemic stroke. Sigma-1 (σ-1) receptor stimulation depresses the activity of ASIC1a channels in cortical neurons, but the mechanism(s) by which σ-1 receptors exert their influence on ASIC1a remains unknown. Experiments were undertaken to elucidate the signaling cascade linking σ-1 receptors to ASIC1a channels. Immunohistochemical studies showed that σ-1 receptors, ASIC1a and A-kinase anchoring peptide 150 colocalize in the plasma membrane of the cell body and processes of cortical neurons. Fluorometric Ca2+ imaging experiments showed that disruption of the macromolecular complexes containing AKAP150 diminished the effects of the σ-1 on ASIC1a, as did application of the calcineurin inhibitors, cyclosporin A and FK-506. Moreover, whole-cell patch clamp experiments showed that σ-1 receptors were less effective at decreasing ASIC1a-mediated currents in the presence of the VIVIT peptide, which binds to calcineurin and prevents cellular effects dependent on AKAP150/calcineurin interaction. The coupling of σ-1 to ASIC1a was also disrupted by preincubation of the neurons in the G-protein inhibitor, pertussis toxin (PTX). Taken together, our data reveal that σ-1 receptor block of ASIC1a function is dependent on activation of a PTX-sensitive G-protein and stimulation of AKAP150 bound calcineurin.

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Abbreviations

AMPA:

(±)-α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid

AM:

Acetoxymethyl ester

ASIC:

Acid-sensing ion channels

CaMKII:

Calcium/calmodulin-dependent protein kinase II

CBP:

Carbetapentane citrate

DMSO:

Dimethyl sulfoxide

DTG:

1,3-Di-o-tolyl-guanidine

PcTx1:

Psalmotoxin1

PSS:

Physiological saline solution

TTX:

Tetrodotoxin

[Ca2+]i :

Intracellular calcium concentration

Δ[Ca2+]i :

Change in intracellular calcium concentration

PKC:

Protein kinase C

PKA:

Protein kinase A

AKAP150:

A-Kinase anchoring protein 150

PTX:

Pertussis toxin

VIVIT:

Nuclear factor of activated T cells inhibitor peptide

BSA:

Bovine serum albumin

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Acknowledgments

Grant support for this work was provided by an AHA Greater Southeast Affiliate Grant-In-Aid Award and a USF Signature Program in Neuroscience Award to J.C. We would like to thank Nivia Cuevas for comments on a draft of this manuscript and Dr. Christopher Leonardo for his assistance with the immunohistochemical experiments. We would also like to thank Mark Lloyd and Joe Johnson from the Analytical Microscopy Core at Moffitt Cancer Center and Research Institute as well as Drs. T. P. Su and Teruo Hayashi for supplying the σ-1 antibody.

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Correspondence to Javier Cuevas.

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Special Issue: In honor of Lynn Wecker.

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Mari, Y., Katnik, C. & Cuevas, J. σ-1 Receptor Inhibition of ASIC1a Channels is Dependent on a Pertussis Toxin-Sensitive G-Protein and an AKAP150/Calcineurin Complex. Neurochem Res 40, 2055–2067 (2015). https://doi.org/10.1007/s11064-014-1324-0

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  • DOI: https://doi.org/10.1007/s11064-014-1324-0

Keywords

  • Sigma-1 receptor
  • ASIC1a
  • Calcineurin
  • AKAP150