title: Coexpression of delta-opioid receptors with micro receptors in GH3 cells changes the functional response to micro agonists from inhibitory to excitatory.
abstract: GH3 cells show spontaneous activity characterized by bursts of action potentials and oscillations in [Ca 2+]i. This activity is modulated by the activation of exogenously expressed opioid receptors. In GH3 cells expressing only micro receptors (GH3MOR cells), the micro receptor-specific ligand [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) inhibited spontaneous Ca 2+ signaling by the inhibition of voltage-gated Ca 2+ channels, activation of inward-rectifying K+ channels, and inhibition of adenylyl cyclase. In contrast, in cells expressing both micro and delta receptors (GH3MORDOR cells), DAMGO had an excitatory effect on Ca 2+ signaling that was mediated by phospholipase C and release of Ca 2+ from intracellular stores. The excitatory effect of DAMGO was also inhibited by pretreatment with pertussis toxin. Despite the excitatory effect on Ca 2+ signaling, DAMGO inhibited Ca 2+ channels and activated inward-rectifying K+ channels in GH3MORDOR cells, although to a lesser extent than in GH3MOR cells. Long-term treatment with the delta receptor-specific ligand [D-Pen2,D-Pen5]-enkephalin reduced the excitatory effect of DAMGO in the majority of GH3MORDOR cells and restored the inhibitory response to DAMGO in some cells. The inhibitory effect of somatostatin on Ca 2+ signaling was not different in GH3MORDOR versus GH3MOR cells. These results indicate that interaction between micro- and delta-opioid receptors causes a change in the functional response to micro ligands, possibly by the formation of a micro/delta heterodimer with distinct functional properties.
authors.affiliation: Department of Neurology, UCLA School of Medicine, Los Angeles, California 90095, USA. acharles@ucla.edu
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Charles
authors.forename: Natalya
authors.initials: N
authors.lastname: Mostovskaya
authors.forename: Kathleen
authors.initials: K
authors.lastname: Asas
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Evans
authors.forename: Megan L
authors.initials: ML
authors.lastname: Dankovich
authors.forename: Tim G
authors.initials: TG
authors.lastname: Hales
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001464:Barium / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D004594:Electrophysiology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D037342:Pertussis Toxin / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013004:Somatostatin / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D014162:Transfection
chemical_list: D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D004963:Estrenes; D011760:Pyrrolidinones; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D001464:Barium; D013004:Somatostatin; D019284:Thapsigargin; D020881:Enkephalin, D-Penicillamine (2,5)-; D037342:Pertussis Toxin; D002118:Calcium