Résumé
The modulation of voltage-dependent Ca
2+
channels at presynaptic nerve terminals is an important factor in the control of neurotransmitter release and synaptic efficacy. Some terminals contain multiple Ca
2+
-channel subtypes (N and P/Q)
1–3
, which are differentially regulated by G-protein activation
4–8
and by protein kinase C (PKC)-dependent phosphorylation
9–11
. Regulation of channel activity by crosstalk between second messenger pathways has been reported
12,13
, although the molecular mechanisms underlying crosstalk have not been described. Here we show that crosstalk occurs at the level of the presynaptic Ca
2+
-channel complex. The α
1
subunit domain I–II linker, which connects the first and second transmembrane domains, contributes to the PKC-dependent upregulation of channel activity, while G-protein-dependent inhibition occurs through binding of Gβλ to two sites in the I–II linker. Crosstalk results from the PKC-dependent phosphorylation of one of the Gβλ binding sites which antagonizes Gβλ-induced inhibition. The results provide a mechanism for the highly regulated and dynamic control of neurotransmitter release that depends on the integration of multiple presynaptic signals.