Inhibition of Ca 2+ channel current by μ‐ and κ‐opioid receptors coexpressed in Xenopus oocytes: desensitization dependence on Ca 2+ channel α 1 subunits

Desensitization of μ‐ and κ‐opioid receptor‐mediated inhibition of voltage‐dependent Ca 2+ channels was studied in a Xenopus oocyte translation system. In the oocytes coexpressing κ‐opioid receptors with N‐ or Q‐type Ca 2+ channel α 1 and β subunits, the κ‐agonist, U50488H, inhibited both neuronal Ca 2+ channel current responses in a pertussis toxin‐sensitive manner and the inhibition was reduced by prolonged agonist exposure. More than 10 min was required to halve the inhibition of Q‐type channels by the κ‐agonist. However, the half‐life for the inhibition of N‐type channels was only 6±1 min. In addition, in the oocytes coexpressing μ‐opioid receptors with N‐type or Q‐type channels, the uncoupling rate of the μ‐receptor‐mediated inhibition of N‐channels was also faster than that of Q‐type channels. In the oocytes coexpressing both μ‐ and κ‐receptors with N‐type channels, stimulation of either receptor resulted in a cross‐desensitization of the subsequent response to the other agonist. Treatment of oocytes with either H‐8 (100 μ M ), staurosporine (400 n M ), okadaic acid (200 n M ), phorbol myristate acetate (5 n M ) or forskolin (50 μ M ) plus phosphodiesterase inhibitor did not affect either the desensitization or the agonist‐evoked inhibition of Ca 2+ channels. These results suggest that the rate of rapid desensitization is dependent on the α 1 subtype of the neuronal Ca 2+ channel, and that a common phosphorylation‐independent mechanism underlies the heterologous desensitization between opioid receptor subtypes.British Journal of Pharmacology (1997) 121 , 806–812; doi: 10.1038/sj.bjp.0701181