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 Ca(2+) 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.

The involvement of the sigma-1 receptor in neurodegeneration and neurorestoration

“…Furthermore, Sig-1Rs stimulate phospholipase C (PLC) resulting in increased levels of IP3 in the cytoplasm (40) with subsequent release of Ca 2þ from the ER via activation of IP3R channels (41). Furthermore, the acid sensing ion channel Ia (42,43), voltage sensitive Ca 2þ channels (44), as well as AMPA and NMDA receptors (45), modulate intracellular Ca 2þ levels and are regulated by Sig-1Rs. Neuroprotection by Sig-1R agonists could therefore be provided by preventing detrimental elevations of intracellular Ca 2þ -mediated effects by these channels.…”

Cocaine inhibits store-operated Ca2+ entry in brain microvascular endothelial cells: critical role for sigma-1 receptors

“…Indeed, Sig-1R has been shown to modulate the functions of p38 MAPK [29], ERK1/2 [30] and calcineurin [31], all of which regulate STIM1 phosphorylation [32–34]. Moreover, both STIM1 [33, 35] and Orai1 [36, 37] are known to be negatively regulated by phosphorylation.…”

Chaperone Sigma1R and Antidepressant Effect

“…Direct interaction between Sigma1Rs and acid-sensing ion channels 1a (ASIC1a) was demonstrated [223,224]. Ligand activation of Sigma1R promotes inhibition of ASICs and decrease in the Ca 2+ influx into rat cortical neurons [225,226]. An antidepressant-like effect of ASIC inhibitors has been demonstrated in various experimental models [76,227].…”