Opioid elevation of intracellular free calcium: Possible mechanisms and physiological relevance

doi:10.1016/j.cellsig.2005.08.005

Cellular Signalling

Volume 18, Issue 2, February 2006, Pages 151-161

https://doi.org/10.1016/j.cellsig.2005.08.005 Get rights and content

Abstract

Opioid receptors are seven transmembrane domain G_i/G₀ protein-coupled receptors, the activation of which stimulates a variety of intracellular signalling mechanisms including activation of inwardly rectifying potassium channels, and inhibition of both voltage-operated N-type Ca²⁺ channels and adenylyl cyclase activity. It is now apparent that like many other G_i/G₀-coupled receptors, opioid receptor activation can significantly elevate intracellular free Ca²⁺ ([Ca²⁺]_i), although the mechanism underlying this phenomenon is not well understood. In some cases opioid receptor activation alone appears to elevate [Ca²⁺]_i, but in many cases it requires concomitant activation of G_q-coupled receptors, which themselves stimulate Ca²⁺ release from intracellular stores via the inositol phosphate pathway. Given the number of Ca²⁺-sensitive processes known to occur in cells, there are therefore a myriad of situations in which opioid receptor-mediated elevations of [Ca²⁺]_i may be important. Here, we review the literature documenting opioid receptor-mediated elevations of [Ca²⁺]_i, discussing both the possible mechanisms underlying this phenomenon and its potential physiological relevance.

Introduction

Ca²⁺ is a ubiquitous intracellular messenger involved in a multitude of processes including neurotransmitter release, muscle contraction, gene transcription, cell proliferation and apoptosis [1], [2]. All of the known opioid receptors (μ, MOR; δ, DOR; κ, KOR and ORL1, NOR) are seven transmembrane domain G protein-coupled receptors that preferentially couple to Pertussis toxin-sensitive inhibitory G_i and G₀ (G_i/G₀) proteins. G_i/G₀-coupled receptor activation is commonly associated with preventing the elevation of intracellular free calcium ([Ca²⁺]_i) by inhibiting voltage-operated Ca²⁺ (VOC) channels in the plasma membrane [3]. However, it has been observed in a diverse range of cell types that opioid receptor activation can also elevate [Ca²⁺]_i. In some instances this is observed during opioid receptor activation alone, but in many cases the opioid receptor-mediated elevation of [Ca²⁺]_i only occurs during concomitant activation of G_q-coupled receptors, which themselves stimulate Ca²⁺ release from intracellular stores via the inositol phosphate pathway [4], [5]. This synergy between opioid and G_q-coupled receptors at the level of [Ca²⁺]_i is not unique to opioid receptors, and appears to represent a novel form of coincident signalling that has been reported for a number of other G_i/G₀-coupled receptors [6]. As yet the underlying mechanisms for this coincident signalling are at best poorly understood.

Here, we review the literature regarding the opioid receptor-mediated elevation of [Ca²⁺]_i and discuss the possible mechanisms underlying this phenomenon. Finally, we discuss the possible relevance of this phenomenon with respect to physiological and pathophysiological functions of the opioid systems.

Section snippets

Ca²⁺ release from intracellular stores

[Ca²⁺]_i can be elevated either by Ca²⁺ release from the intracellular stores of the endoplasmic reticulum (ER) or by Ca²⁺ influx across the plasma membrane [1]. In most of the cell types studied, G_i/G₀-coupled receptor activation appears to elevate [Ca²⁺]_i by stimulating the release of Ca²⁺ from the ER [6]. Experimentally this can be demonstrated in two ways. First, by observing whether the G_i/G₀-coupled receptor-mediated elevation of [Ca²⁺]_i persists in the absence of extracellular Ca²⁺ and

Role of concomitant G_q-coupled receptor activation

In neurons, neuronal cell lines, astrocytes, smooth muscle cells and mammalian expression systems, G_i/G₀-coupled receptor activation alone often does not elevate [Ca²⁺]_i. However, in these same cell types G_i/G₀-coupled receptor activation does stimulate a rise in [Ca²⁺]_i when there is a concomitant activation of G_q-coupled receptors [4], [5], [9], [12], [19], [20], [21], [22], [23], [24], [25] (Fig. 1). As yet, no single mechanism for this novel coincident signalling between G_i/G₀-coupled and G_q

Neurotransmission

The contribution of opioid receptor-mediated Ca²⁺ elevations to opioid receptor function in the intact animal is far from clear, although there is compelling evidence that key Ca²⁺ signalling molecules are important in mediating opioid-induced antinociception. Knock-out mice lacking the gene for PLCβ3 exhibit a reduced sensitivity to morphine [77]. Similarly, in wild type mice treated with the InsP₃ receptor antagonist, Xestospongin, or in opisthonos heterozygote mice expressing abnormally low

Concluding remarks

The ability of opioid receptors to elevate [Ca²⁺]_i has been well documented in both neuronal and non-neuronal cell types but the mechanisms by which this occurs remain poorly characterised. What is apparent is that in many cases the opioid-mediated elevation of [Ca²⁺]_i often occurs as a result of synergy with other Ca²⁺ release signalling pathways, principally the G_q-coupled receptor-activated inositol phosphate pathway, suggesting that opioid receptors may play a novel modulatory role in the

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ReviewOpioid elevation of intracellular free calcium: Possible mechanisms and physiological relevance

Abstract

Introduction

Section snippets

Ca2+ release from intracellular stores

Role of concomitant Gq-coupled receptor activation

Neurotransmission

Concluding remarks

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Review
Opioid elevation of intracellular free calcium: Possible mechanisms and physiological relevance

Ca²⁺ release from intracellular stores

Role of concomitant G_q-coupled receptor activation