A118G Mu Opioid Receptor polymorphism increases inhibitory effects on CaV2.2 channels

Abstract

Single nucleotide polymorphisms (SNPs) in the human OPRM1 gene result in common variants of Mu Opioid Receptors (hMORs). The A118G SNP occurs at high frequency in certain human populations and produces an aminoacidic substitution: N40D (hMOR-N to hMOR-D) at protein level. N40D is reported to alter pain thresholds and morphine efficacy. hMORs inhibit CaV2.2 channels (N-type currents) at presynaptic nociceptor terminals in dorsal horn, thus reducing calcium influx, transmitter release, and transmission of noxious signals. Nociceptors express different splice isoforms of CaV2.2. Isoforms distinguished by the presence of alternatively spliced exon e37a are of interest because channels containing e37a are particularly enriched in nociceptors. Recent studies showed that CaV2.2e37a is more sensitive to inhibition by Mu Opioid Receptors than the ubiquitous splice variant CaV2.2e37b. Here, we evaluate the effect of hMOR-N and hMOR-D on cloned CaV2.2e37a channels expressed in mammalian cells. We observe that hMOR-D inhibits CaV2.2e37a currents at agonist concentrations 4-fold lower than those needed to inhibit CaV2.2e37a currents by the same degree via hMOR-N. We observe little difference in hMOR-D and hMOR-N inhibition of CaV2.2e37b currents. Our study demonstrates that this common site of OPRM1 polymorphism affects the inhibitory actions of MORs on both major CaV2.2 isoforms expressed in nociceptors.