ORL1 receptor–mediated internalization of N-type calcium channels

Abstract

The inhibition of N-type calcium channels by opioid receptor like receptor 1 (ORL1) is a key mechanism for controlling the transmission of nociceptive signals. We recently reported that signaling complexes consisting of ORL1 receptors and N-type channels mediate a tonic inhibition of calcium entry. Here we show that prolonged ( approximately 30 min) exposure of ORL1 receptors to their agonist nociceptin triggers an internalization of these signaling complexes into vesicular compartments. This effect is dependent on protein kinase C activation, occurs selectively for N-type channels and cannot be observed with mu-opioid or angiotensin receptors. In expression systems and in rat dorsal root ganglion neurons, the nociceptin-mediated internalization of the channels is accompanied by a significant downregulation of calcium entry, which parallels the selective removal of N-type calcium channels from the plasma membrane. This may provide a new means for long-term regulation of calcium entry in the pain pathway.

Development of Purkinje cell degeneration in a knockin mouse model reveals lysosomal involvement in the pathogenesis of SCA6

“…The mechanisms that control the degradation of Ca v 2.1 are not well understood. It has been shown that Ca v 1.2 and Ca v 2.2 undergo internalization and translocation to lysosome for degradation in response to activation of either the NMDA receptor or the nociceptin receptor (23,24). Therefore, although the mechanisms by which Ca v 2.1 is internalized remain elusive, it is likely that Ca v 2.1 is also sequestered to lysosome for degradation.…”

G protein inhibition of CaV2 calcium channels

“…31,32 All of these mechanisms terminate G protein signaling and thus channel modulation, but in some cases, direct GPCR-Ca V 2 interactions have been demonstrated that result in endocytic removal of the channel from the plasma membrane upon GPCR desensitization. [33][34][35] Inhibition of Ca 2+ Channels by G Protein βγ…”

“…Voltage-independent inhibition is generally less well characterized and likely comprised of several distinct mechanisms including channel trafficking, phosphorylation and lipid signaling pathways (reviewed in ref. 34,35,40,[43][44][45][46][47][48]. The primary focus of this review is the direct, voltage-dependent inhibition of Ca V 2 channels.…”

“…133 Mutation of several residues on the Gα interacting surface disrupt inhibition of Ca V 2 channels, 76,122,134,135 but residues on the opposite face of Gβ 1 have also been implicated. [135][136][137] Moreover, Asn 35 and Asn 36 on Gβ 1 have been shown to underlie the ability of PKC to antagonize inhibition of Ca V 2.2. 136 Given that Thr 422 on the rat Ca V 2.2 I-II linker has been and/or transduction of Gβγ binding into inhibition.…”

“…Constitutive activity of the receptors leads to tonic voltage-dependent inhibition, and upon prolonged agonist application the channel is internalized as a consequence of desensitization of the coupled ORL1 receptor. 35,182 More recently it has been shown that ORL1 and classic opioid receptors (e.g., μ-opioid receptors) can heterodimerize. One notable consequence of this is that μ-opioid receptor agonists lead to internalization of the GPCR-channel complex, which does not occur in the absence of the ORL1 receptor.…”