σ Receptor Activation Blocks Potassium Channels and Depresses Neuroexcitability in Rat Intracardiac Neurons

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101

Sigma receptors are putative targets for neuroprotection following ischemia; however, little is known on their mechanism of action. One of the key components in the demise of neurons following ischemic injury is the disruption of intracellular calcium homeostasis. Fluorometric calcium imaging was used to examine the effects of sigma receptor activation on changes in intracellular calcium concentrations ([Ca 2ϩ ] i ) evoked by in vitro ischemia in cultured cortical neurons from embryonic rats. The sigma receptor agonist, 1,3-di-o-tolyl-guanidine (DTG), was shown to depress [Ca 2ϩ ] i elevations observed in response to ischemia induced by sodium azide and glucose deprivation. Two sigma receptor antagonists, metaphitwere shown to blunt the ability of DTG to inhibit ischemiaevoked increases in [Ca 2ϩ ] i , revealing that the effects are mediated by activation of sigma receptors and not via the actions of DTG on nonspecific targets such as N-methyl-D-aspartate receptors. DTG inhibition of ischemia-induced increases in [Ca 2ϩ ] i was mimicked by the -1 receptor-selective agonists, carbetapentane, (ϩ)-pentazocine and PRE-084 [2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate hydrochloride], but not by the sigma-2-selective agonist, ibogaine, showing that activation of sigma-1 receptors is responsible for the effects. In contrast, DTG, carbetapentane, and ibogaine blocked spontaneous, synchronous calcium transients observed in our preparation at concentrations consistent with sigma receptormediated effects, indicating that both sigma-1 and sigma-2 receptors regulate events that affect [Ca 2ϩ ] i in cortical neurons. Our studies show that activation of sigma receptors can ameliorate [Ca 2ϩ ] i dysregulation associated with ischemia in cortical neurons and, thus, identify one of the mechanisms by which these receptors may exert their neuroprotective properties.Sigma receptors are widely distributed in the mammalian brain, and these receptors recognize a diverse array of centrally acting substances including opiates, antipsychotics, antidepressants, phencyclidine (PCP)-related compounds, and neurosteroids Bowen, 2000). Thus far, two sigma receptor subtypes have been identified on the basis of their pharmacological profile, with the sigma-1 receptor showing high affinity for the positive isomer of bezomorphas such as (ϩ)-pentazocine and (ϩ)-SKF-10,047, and the sigma-2 receptor having high affinity for ibogaine (Vilner and Bowen, 2000), but only the sigma-1 receptor has been cloned (Hanner et al., 1996). Sigma receptors have been implicated in numerous physiological and pathophysiological processes such as learning and memory (Senda et al., 1996), movement disorders , and drug addiction (McCracken et al., 1999). These receptors are emerging as therapeutic targets for various diseases such neuropsychiatric disorders and cancer (Casellas et al., 2004;Hayashi and Su, 2004). Moreover, the observation that several sigma receptor ligands are neuroprotective in both in vivo and in vitro models of ischemia has ...

Section: Discussionsupporting

confidence: 62%

Sigma-1 Receptor Activation Prevents Intracellular Calcium Dysregulation in Cortical Neurons during in Vitro Ischemia

Katnik

Guerrero

Pennypacker

et al. 2006

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101

“…It has been shown in neurohypophysial nerve terminals (Wilke et al, 1999) that K ϩ currents are modulated by different 1 -receptor ligands. Furthermore, the activation of 1 receptors has recently been shown to depress the excitability of rat intracardiac neurons (Zhang and Cuevas, 2005). Finally, the direct protein-protein interaction of the 1 receptor and a K ϩ channel was demonstrated recently by Aydar et al (2002).…”

Section: Discussionmentioning

confidence: 99%

σ₂-Receptor Ligand-Mediated Inhibition of Inwardly Rectifying K⁺ Channels in the Heart

Monassier¹,

Manoury²,

Bellocq³

et al. 2007

The 2 -receptor agonist, ifenprodil, was suggested as an inhibitor of G protein-coupled inwardly rectifying potassium channels. Nevertheless, an analysis of the role of 2 receptors in cardiac electrophysiology has never been done. This work aims i) to identify the roles of cardiac 2 receptors in the regulation of cardiac K ϩ channel conductances and ii) to check whether 2 -receptor agonists exhibit class III antiarrhythmic properties. , and 1,3-di(2-tolyl)guanidine were used to discriminate the effects linked to 2 receptors from those of the 1 subtype, induced by (Ϯ)-N-allylnormetazocine (SKF-10,047). The 2 -receptor antagonist 3-␣-tropanyl-2(pCl-phenoxy)butyrate (SM-21) was employed to characterize 2 -mediated effects in patchclamp experiments. In rabbits, all 2 -receptor agonists reduced phenylephrine-induced cardiac arrhythmias. They prolonged action potential duration in rabbit Purkinje fibers and reduced human ether-a-go-go-related gene (HERG) K ϩ currents. (ϩ)-SKF-10,047 was completely inactive in the last two tests. The effects of threoifenprodil were not antagonized by SM-21. In HERG-transfected COS-7 cells, SM-21 potentiated the ifenprodil-induced blockade of the HERG current. These data suggest that 2 -receptor ligands block I Kr and that this effect could explain part of the antiarrhythmic properties of this ligands family. Nevertheless, an interaction with HERG channels not involving 2 receptors seems to share this pharmacological property. This work shows for the first time that particular caution has to be taken toward ligands with affinity for 2 receptors. The repolarization prolongation and the earlyafterdepolarization can be responsible for "torsades de pointe" and sudden cardiac death.

“…Metaphit has been shown to bind irreversibly to -1 receptors with an IC 50 value of 50 M (Wu et al, 2003). Preincubation in metaphit blocks -1 re- ceptor-mediated modulation of voltage-gated K ϩ channels in intracardiac neurons and depression of ischemia-induced elevations in [Ca 2ϩ ] i in cortical neurons (Zhang and Cuevas, 2005;Katnik et al, 2006). Preincubation of cortical neurons in 50 M metaphit antagonized CBP inhibition of ASIC1a by ϳ40%.…”

Section: Discussionmentioning

confidence: 99%

σ-1 Receptor Modulation of Acid-Sensing Ion Channel a (ASIC1a) and ASIC1a-Induced Ca²⁺ Influx in Rat Cortical Neurons

Herrera

Katnik²,

Rodriguez³

et al. 2008

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Acid-sensing ion channels (ASICs) are proton-gated cation channels found in peripheral and central nervous system neurons. The ASIC1a subtype, which has high Ca 2ϩ permeability, is activated by ischemia-induced acidosis and contributes to the neuronal loss that accompanies ischemic stroke. Our laboratory has shown that activation of receptors depresses ion channel activity and [Ca 2ϩ ] i dysregulation during ischemia, which enhances neuronal survival. Whole-cell patch-clamp electrophysiology and fluorometric Ca 2ϩ imaging were used to determine whether receptors regulate the function of ASIC in cultured rat cortical neurons. Bath application of the selective ASIC1a blocker, psalmotoxin1, decreased proton-evoked [Ca 2ϩ ] i transients and peak membrane currents, suggesting the presence of homomeric ASIC1a channels. The pan-selective -1/-2 receptor agonists, 1,3-di-o-tolyl-guanidine (100 M) and opipramol (10 M), reversibly decreased acid-induced elevations in [Ca 2ϩ ] i and membrane currents. Pharmacological experiments using receptor-subtype-specific agonists demonstrated that -1, but not -2, receptors inhibit ASIC1a-induced Ca 2ϩ elevations. These results were confirmed using the irreversible receptor antagonist metaphit (50 M) and the selective -1 antagonist BD1063 (10 nM), which obtunded the inhibitory effects of the -1 agonist, carbetapentane. Activation of ASIC1a was shown to stimulate downstream Ca 2ϩ influx pathways, specifically N-methyl-D-aspartate and (Ϯ)-␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate receptors and voltage-gated Ca 2ϩ channels. These subsequent Ca 2ϩ influxes were also inhibited upon activation of -1 receptors. These findings demonstrate that -1 receptor stimulation inhibits ASIC1a-mediated membrane currents and consequent intracellular Ca 2ϩ accumulation. The ability to control ionic imbalances and Ca 2ϩ dysregulation evoked by ASIC1a activation makes receptors an attractive target for ischemic stroke therapy.Acid-sensing ion channels are a class of ligand-gated channels that are members of the degenerin/epithelial sodium channel superfamily and are expressed in both peripheral and central nervous system neurons . Thus far, four genes (ASIC1-ASIC4) and two splice variants of ASIC1 and ASIC2 (a and b) have been cloned ) that encode protein subunits that form functional proton-gated homomultimeric or heteromultimeric channels . The pH of half-maximal activation and the tissue expression patterns differ between each channel subtype.One of the most common ASIC subtypes in the central nervous system (CNS) contains the ASIC1a subunit, which can form homomultimeric or heteromultimeric channels with ASIC2a . These channels are activated by pH Յ 7 and have a pH of half-maximal activation of ϳ6.0