Phe27Cys polymorphism of the human delta opioid receptor predisposes cells to compromised calcium signaling.
Summary of "Phe27Cys polymorphism of the human delta opioid receptor predisposes cells to compromised calcium signaling."
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 (hδOR(Cys27)) instead of the evolutionary conserved phenylalanine (hδOR(Phe27)). The two variants have indistinguishable pharmacological properties but, importantly, hδOR(Cys27) differs from hδOR(Phe27) 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 Ca(2+) ATPase (SERCA) 2b in the early phase of their biosynthesis. We analyzed by pulse-chase assays, whether cellular signaling can affect hδOR(Cys27) maturation. Neither activation of the receptor by a δOR-specific agonist Leu-enkephalin, induction of intracellular calcium (Ca(2+)) 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 Ca(2+) measurements that over-expression of hδOR(Cys27), but not hδOR(Phe27), compromised ATP-induced intracellular Ca(2+)-signaling. Furthermore, hδOR(Cys27) precursors showed slower dissociation from SERCA2b and hδOR(Cys27) 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 hδOR(Cys27) encoding allele might have lowered threshold for Ca(2+) dysregulation in neurons expressing hδOR.
Affiliation
Department of Anatomy and Cell Biology, Institute of Biomedicine, University of Oulu, P.O. Box 5000, FI-90014, Oulu, Finland, Jussi.Tuusa@oulu.fi.
Journal Details
This article was published in the following journal.
Name: Molecular and cellular biochemistry
ISSN: 1573-4919
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/21234650
- DOI: http://dx.doi.org/10.1007/s11010-011-0725-5
Medical and Biotech [MESH] Definitions
Enkephalin, D-penicillamine (2,5)-
A disulfide opioid pentapeptide that selectively binds to the DELTA OPIOID RECEPTOR. It possesses antinociceptive activity.
Receptors, Opioid, Delta
A class of opioid receptors recognized by its pharmacological profile. Delta opioid receptors bind endorphins and enkephalins with approximately equal affinity and have less affinity for dynorphins.
Receptors, Opioid
Cell membrane proteins that bind opioids and trigger intracellular changes which influence the behavior of cells. The endogenous ligands for opioid receptors in mammals include three families of peptides, the enkephalins, endorphins, and dynorphins. The receptor classes include mu, delta, and kappa receptors. Sigma receptors bind several psychoactive substances, including certain opioids, but their endogenous ligands are not known.
Buprenorphine
A derivative of the opioid alkaloid THEBAINE that is a more potent and longer lasting analgesic than MORPHINE. It appears to act as a partial agonist at mu and kappa opioid receptors and as an antagonist at delta receptors. The lack of delta-agonist activity has been suggested to account for the observation that buprenorphine tolerance may not develop with chronic use.
Enkephalin, Leucine-2-alanine
A delta-selective opioid (ANALGESICS, OPIOID). It can cause transient depression of mean arterial blood pressure and heart rate.
PubMed Articles
Mouse Delta Opioid Receptors are Located on Presynaptic Afferents to Hippocampal Pyramidal Cells.
Delta opioid receptors participate in the control of chronic pain and emotional responses. Recent data have also identified their implication in drug-context associations pointing to a modulatory role...
Mu and delta opioid receptors modulate the reinforcing effects of ethanol, however, their role in the subjective effects of ethanol is not well understood. This study evaluated the contribution of mu...
To determine if carriers of the allelic expression of the G variant of the human mu opioid receptor (OPRM1) A118G polymorphism have greater increases in striatal dopamine (DA) release after tobacco sm...
Arylphenylpyrrolidinylmethylphenoxybenzamides were found to have high affinity and selectivity for κ opioid receptors. On the basis of receptor binding assays in Chinese hamster ovary (CHO) cells exp...
Evolution of the opioid/ORL-1 receptor gene family.
In gnathostomes the kappa, mu, delta, ORL-1 receptor genes constitute the opioid/ORL-1 receptor gene family. These genes are most likely the result of two (2R) genome duplication events that occurred...
Clinical Trials
Mu-Opioid Receptor Genetic Polymorphism and Intrathecal Analgesia
Pharmocogenetics has allowed clinicians to identify associations between an individual's genetic profile and his/her response to drugs. The A118G (c.188A>G)is a single nucleotide polymorp...
Effects of Nicotine on Brain Opioid Receptors
A substantial body of evidence implicates the endogenous opioid system, and the mu opioid receptor (MOR) in particular, in the reinforcing effects of drugs of abuse, including nicotine. A...
The protein polymorphism of the growth hormone receptor characterized by the genomic deletion of exon 3 has been linked to the magnitude of the first-year-growth response to growth hormone...
At present, there is some clinical data for different functional response to beta-blockers associated with beta-adrenergic receptor polymorphisms. But there has been no data reported, abou...
Immunotherapy of Hepatocellular Carcinoma With Gamma Delta T Cells
For most patients with hepatocellular carcinoma, surgery or other curative procedures are not possible and only palliative measures could be applied (chemoembolization, targeted drugs, bes...
