PT - JOURNAL ARTICLE AU - Andrew C. Charles AU - Natalya Mostovskaya AU - Kathleen Asas AU - Christopher J. Evans AU - Megan L. Dankovich AU - Tim G. Hales TI - Coexpression of δ-Opioid Receptors with μ Receptors in GH<sub>3</sub> Cells Changes the Functional Response to μ Agonists from Inhibitory to Excitatory AID - 10.1124/mol.63.1.89 DP - 2003 Jan 01 TA - Molecular Pharmacology PG - 89--95 VI - 63 IP - 1 4099 - http://molpharm.aspetjournals.org/content/63/1/89.short 4100 - http://molpharm.aspetjournals.org/content/63/1/89.full SO - Mol Pharmacol2003 Jan 01; 63 AB - GH3 cells show spontaneous activity characterized by bursts of action potentials and oscillations in [Ca2+]i. This activity is modulated by the activation of exogenously expressed opioid receptors. In GH3 cells expressing only μ receptors (GH3MOR cells), the μ receptor-specific ligand [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) inhibited spontaneous Ca2+ signaling by the inhibition of voltage-gated Ca2+ channels, activation of inward-rectifying K+ channels, and inhibition of adenylyl cyclase. In contrast, in cells expressing both μ and δ receptors (GH3MORDOR cells), DAMGO had an excitatory effect on Ca2+ signaling that was mediated by phospholipase C and release of Ca2+ from intracellular stores. The excitatory effect of DAMGO was also inhibited by pretreatment with pertussis toxin. Despite the excitatory effect on Ca2+ signaling, DAMGO inhibited Ca2+ channels and activated inward-rectifying K+ channels in GH3MORDOR cells, although to a lesser extent than in GH3MOR cells. Long-term treatment with the δ 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 Ca2+ signaling was not different in GH3MORDOR versus GH3MOR cells. These results indicate that interaction between μ- and δ-opioid receptors causes a change in the functional response to μ ligands, possibly by the formation of a μ/δ heterodimer with distinct functional properties.