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Coexpression of δ-Opioid Receptors with μ Receptors in GH 3 Cells Changes the Functional Response to μ Agonists from Inhibitory to Excitatory

2003; American Society for Pharmacology and Experimental Therapeutics; Volume: 63; Issue: 1 Linguagem: Inglês

10.1124/mol.63.1.89

1521-0111

Andrew Charles, Natalya Mostovskaya, Kathleen Asas, Christopher J. Evans, Megan L. Dankovich, Tim G. Hales,

Pharmacological Receptor Mechanisms and Effects

GH 3 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 GH 3 cells expressing only μ receptors (GH 3 MOR cells), the μ receptor-specific ligand [d-Ala 2 , N -Me-Phe 4 ,Gly 5 -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 μ and δ receptors (GH 3 MORDOR 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 GH 3 MORDOR cells, although to a lesser extent than in GH 3 MOR cells. Long-term treatment with the δ receptor-specific ligand [d-Pen 2 ,d-Pen 5 ]-enkephalin reduced the excitatory effect of DAMGO in the majority of GH 3 MORDOR cells and restored the inhibitory response to DAMGO in some cells. The inhibitory effect of somatostatin on Ca 2+ signaling was not different in GH 3 MORDOR versus GH 3 MOR 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.