Abstract
1. Desensitization of mu- and kappa-opioid receptor-mediated inhibition of voltage-dependent Ca2+ channels was studied in a Xenopus oocyte translation system. 2. In the oocytes coexpressing kappa-opioid receptors with N- or Q-type Ca2+ channel alpha 1 and beta subunits, the kappa-agonist, U50488H, inhibited both neuronal Ca2+ channel current responses in a pertussis toxin-sensitive manner and the inhibition was reduced by prolonged agonist exposure. 3. More than 10 min was required to halve the inhibition of Q-type channels by the kappa-agonist. However, the half-life for the inhibition of N-type channels was only 6 +/- 1 min. In addition, in the oocytes coexpressing mu-opioid receptors with N-type or Q-type channels, the uncoupling rate of the mu-receptor-mediated inhibition of N-channels was also faster than that of Q-type channels. 4. In the oocytes coexpressing both mu- and kappa-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 microM), staurosporine (400 nM), okadaic acid (200 nM), phorbol myristate acetate (5 nM) or forskolin (50 microM) plus phosphodiesterase inhibitor did not affect either the desensitization or the agonist-evoked inhibition of Ca2+ channels. 5. These results suggest that the rate of rapid desensitization is dependent on the alpha 1 subtype of the neuronal Ca2+ channel, and that a common phosphorylation-independent mechanism underlies the heterologous desensitization between opioid receptor subtypes.