Coexpression of δ-Opioid Receptors with μ Receptors in GH3 Cells Changes the Functional Response to μ Agonists from Inhibitory to Excitatory

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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.