Calcium Channels Brought Inside by Opioid-Like Receptor

Abstract

Nociceptin is an endogenous pain-alleviating peptide that binds to the receptor ORL1, which is structurally similar to opioid receptors. ORL1 was recently found to interact directly with N-type calcium channels, resulting in tonic, agonist-independent inhibition. Altier et al. extend these observations and report that extended exposure to nociceptin stimulated the internalization of both ORL1 and N-type calcium channels, thereby decreasing calcium signaling. Initial experiments performed with transfected cells--imaging analysis and biochemical assays for cell surface versus internal pools of the receptor and channel--indicated that prolonged nociceptin exposure of cells expressing tagged forms ORL1 and Cav2.2 resulted in their internalization and their accumulation in acidic, lysosomal, and endosomal structures. The internalization was specific for the Cav2.2 channel and the ORL1 receptor and did not occur if ORL1 was coexpressed with other types of channels or if Cav2.2 was expressed with other opioid receptors or the G protein-coupled receptor angiotensin receptor 1 (ATR1). Analysis of dorsal root ganglion (DRG) neurons indicated that nociceptin treatment promoted the redistribution of N-type calcium channels in a subset of neurons (presumably the 10% in which ORL1 was present) from the cell surface to punctate internal structures. In the transfected cells, N-type channel current density was decreased by prolonged exposure to nociceptin. In cultured DRG neurons, one population of cells exhibited a pronounced inhibition of calcium signal after 30-minute nociceptin exposure. The abundance of the pool of cells that showed inhibition was the same as the abundance of ORL1-positive cells in the culture, which is consistent with the inhibited cells being the ones expressing ORL1. This cointernalization represents a novel mechanism for regulation of calcium channel activity and has implications for pain management and understanding the molecular mechanisms underlying tolerance to opioid pain relievers. C. Altier, H. Khosravani, R. M. Evans, S. Hameed, J. B. Peloquin, B. A. Vartian, L. Chen, A. M. Beedle, S. S. G. Ferguson, A. Mezghrani, S. J. Dubel, E. Bourinet, J. E. McRory, G. W. Zamponi, ORL1 receptor-mediated internalization of N-type calcium channels. Nat. Neurosci. 9 , 31-40 (2005). [PubMed]