Sigma receptors: from discovery to highlights of their implications in the cardiovascular system

Monassier, Laurent; Bousquet, Pascal

doi:10.1046/j.1472-8206.2002.00063.x

Cited by 45 publications

(38 citation statements)

References 40 publications

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“…Such effects may in part be due to activation of receptors on intracardiac neurons. Similarly, various drugs that act on receptors, such as haloperidol, have significant effects on the heart (Monassier and Bousquet, 2002). Our observations raise the possibility that the cardiovascular effects of these compounds may be mediated by their modulation of the electrical activity of intrinsic cardiac neurons.…”

Section: Zhang and Cuevasmentioning

confidence: 78%

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

Zhang¹,

Cuevas²

2005

J Pharmacol Exp Ther

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The receptors have been implicated in the regulation of the cardiovascular system, and -1 receptor transcripts have been found in parasympathetic intracardiac neurons. However, the cellular function of -1 receptors in these cells remains to be determined. Effects of receptor activation on voltage-activated K ϩ channels and action potential firing were studied in isolated intracardiac neurons using whole-cell patch-clamp recording techniques. Activation of receptors reversibly blocked delayed outwardly rectifying potassium channels, large conductance Ca 2ϩ -sensitive K ϩ channels, and the Mcurrent with maximal inhibition Ͼ80%. The inhibition of K ϩ channels by ligands was dose-dependent, and the rank order potency of (ϩ)-pentazocine Ͼ ibogaine Ͼ 1,3-di-O-tolyguanidin (DTG) suggests that the effect is mediated by -1 receptor activation. Preincubation of neurons with the irreversible receptor antagonist metaphit blocked DTG-induced inhibition of K ϩ channels, confirming that the effect is mediated by receptor activation. Although bath application of ligands depolarized intracardiac neurons, the number of action potentials fired by the cells in response to depolarizing current pulses was decreased in the presence of these drugs. Neither dialysis of the neurons nor application of intracellular 5Ј-O-(2-thiodiphosphate) trilithium salt inhibited the effect of receptors on K ϩ channels, which suggests that the signal transduction pathway does not involve a diffusible cytosolic second messenger or a G protein. Together, these data suggest that -1 receptors are directly coupled to K ϩ channels in intracardiac neurons. Furthermore, activation of -1 receptors depresses the excitability of intracardiac neurons and is thus likely to block parasympathetic input to the heart.

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Section: Zhang and Cuevasmentioning

confidence: 78%

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

Zhang¹,

Cuevas²

2005

J Pharmacol Exp Ther

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“…28 However, even today the precise role of the receptors is quite ambiguous since they have been implicated in many therapeutic areas such as cardiology, psychiatry, immunology, and oncology. 29 The correlation between castoreum’s affinities to the sigma receptors and its therapeutic effects thus remains obscure at this point.…”

Section: Resultsmentioning

confidence: 99%

Enantiospecific Synthesis and Biological Investigations of a Nuphar Alkaloid: Proposed Structure of a Castoreum Component

Seki

Georg

2014

Eur J Org Chem

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An enantiospecific synthesis of a Nuphar alkaloid was achieved in 9 steps from N-Boc-(L)-proline. The alkaloid is a minor component of castoreum, the dried scent glands of the beaver. During the course of our study, the stereochemistry of three synthetic intermediates was verified by X-ray analysis, which contributes to resolving existing discrepancies among the literature reports regarding the synthesis of this particular compound. Based on our synthesis, we propose the structure of the natural product. Also, intrigued by castoreum’s therapeutic effect, which was used in ancient Greece and Rome for gynecological and other purposes, biological screening was conducted. We found that the alkaloid has affinity for the oxytocin receptor.

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“…-Receptor ligands have profound effects on function in the brain as well as the heart (19,21,35). Progesterone block of -receptors in the brain could play a role in the differences in mood and behavior associated with reproductive state (31,42,46).…”

Section: Discussionmentioning

confidence: 99%

Antagonist action of progesterone at σ-receptors in the modulation of voltage-gated sodium channels

Johannessen¹,

Fontanilla

Mavlyutov

et al. 2011

American Journal of Physiology-Cell Physiology

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σ-Receptors are integral membrane proteins that have been implicated in a number of biological functions, many of which involve the modulation of ion channels. A wide range of synthetic ligands activate σ-receptors, but endogenous σ-receptor ligands have proven elusive. One endogenous ligand, dimethyltryptamine (DMT), has been shown to act as a σ-receptor agonist. Progesterone and other steroids bind σ-receptors, but the functional consequences of these interactions are unclear. Here we investigated progesterone binding to σ(1)- and σ(2)-receptors and evaluated its effect on σ-receptor-mediated modulation of voltage-gated Na(+) channels. Progesterone binds both σ-receptor subtypes in liver membranes with comparable affinities and blocks photolabeling of both subtypes in human embryonic kidney 293 cells that stably express the human cardiac Na(+) channel Na(v)1.5. Patch-clamp recording in this cell line tested Na(+) current modulation by the σ-receptor ligands ditolylguanidine, PB28, (+)SKF10047, and DMT. Progesterone inhibited the action of these ligands to varying degrees, and some of these actions were reduced by σ(1)-receptor knockdown with small interfering RNA. Progesterone inhibition of channel modulation by drugs was consistent with stronger antagonism of σ(2)-receptors. By contrast, progesterone inhibition of channel modulation by DMT was consistent with stronger antagonism of σ(1)-receptors. Progesterone binding to σ-receptors blocks σ-receptor-mediated modulation of a voltage-gated ion channel, and this novel membrane action of progesterone may be relevant to changes in brain and cardiovascular function during endocrine transitions.

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Sigma receptors: from discovery to highlights of their implications in the cardiovascular system

Cited by 45 publications

References 40 publications

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

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

Enantiospecific Synthesis and Biological Investigations of a Nuphar Alkaloid: Proposed Structure of a Castoreum Component

Antagonist action of progesterone at σ-receptors in the modulation of voltage-gated sodium channels

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