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Phe27Cys polymorphism of the human delta opioid receptor predisposes cells to compromised calcium signaling

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Abstract

A quarter of the human population with European background carries at least one allele of the OPRD1 gene that encodes the delta opioid receptor with cysteine at the amino acid position 27 (hδORCys27) instead of the evolutionary conserved phenylalanine (hδORPhe27). The two variants have indistinguishable pharmacological properties but, importantly, hδORCys27 differs from hδORPhe27 in having low maturation efficiency, lower stability at the cell surface and pronounced intracellular location. Both variants were previously shown to interact with the Sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) 2b in the early phase of their biosynthesis. We analyzed by pulse-chase assays, whether cellular signaling can affect hδORCys27 maturation. Neither activation of the receptor by a δOR-specific agonist Leu-enkephalin, induction of intracellular calcium (Ca2+) release by ATP nor the direct stimulation of SERCA 2b by protein kinase C activation affected receptor maturation in HEK-293 cells. No signaling-mediated regulation of receptor maturation could therefore be demonstrated. Instead, we found by using single cell Ca2+ measurements that over-expression of hδORCys27, but not hδORPhe27, compromised ATP-induced intracellular Ca2+-signaling. Furthermore, hδORCys27 precursors showed slower dissociation from SERCA2b and hδORCys27 expression caused down-regulation of the homocysteine-inducible endoplasmic reticulum-resident ubiquitin domain-like member 1 protein (HERP). We suggest that aging individuals with at least one hδORCys27 encoding allele might have lowered threshold for Ca2+ dysregulation in neurons expressing hδOR.

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Acknowledgments

We are grateful to Tarja Leskelä for cloning of the HA-hδORCys27–pcDNA3 plasmid construct. This study was supported by grants from the Academy of Finland (#127199) and the Sigrid Juselius Foundation (UEP-R). The Finnish Cultural foundation is acknowledged for the grant to J.T.T.

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  1. Department of Anatomy and Cell Biology, Institute of Biomedicine, University of Oulu, P.O. Box 5000, FI-90014, Oulu, Finland

    Jussi T. Tuusa & Ulla E. Petäjä-Repo

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  1. Jussi T. Tuusa
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  2. Ulla E. Petäjä-Repo
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Correspondence to Jussi T. Tuusa.

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Tuusa, J.T., Petäjä-Repo, U.E. Phe27Cys polymorphism of the human delta opioid receptor predisposes cells to compromised calcium signaling. Mol Cell Biochem 351, 173–181 (2011). https://doi.org/10.1007/s11010-011-0725-5

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  • DOI: https://doi.org/10.1007/s11010-011-0725-5

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