Résumé
The modulation of a family of cloned neuronal calcium channels by stimulation of a coexpressed μ opioid receptor was studied by transient expression in Xenopus oocytes. Activation of the morphine receptor with the synthetic enkephalin [D-Ala2,N-Me-Phe4,Gly-ol$^{5 }$] enkephalin (DAMGO) resulted in a rapid inhibition of α1A(by ≈ 20%) and α1B(by ≈ 55%) currents while α1Cand α1Ecurrents were not significantly affected. The opioid-induced effects on α1Aand α1Bcurrents were blocked by pertussis toxin and the GTP analogue guanosine 5′-[β -thio]diphosphate. Similar to modulation of native calcium currents, DAMGO induced a slowing of the activation kinetics and exhibited a voltage-dependent inhibition that was partially relieved by application of strong depolarizing pulses. α1Acurrents were still inhibited in the absence of coexpressed Ca channel α2and β subunits, suggesting that the response is mediated by the α1subunit. Furthermore, the sensitivity of α1Acurrents to DAMGO-induced inhibition was increased ≈ 3-fold in the absence of a β subunit. Overall, the results show that the α1A(P/Q type) and the α1B(N type) calcium channels are selectively modulated by a GTP-binding protein (G protein). The results raise the possibility of competitive interactions between β subunit and G protein binding to the α1subunit, shifting gating in opposite directions. At presynaptic terminals, the G protein-dependent inhibition may result in decreased synaptic transmission and play a key role in the analgesic effect of opioids and morphine.