Résumé
About 10 years ago, a yeast two-hybrid screen highlighted the unexpected interaction between the regulatory subunit of the voltage–gated Ca2+ channels, CaVβ, and Kir/Gem, a member of the recently identified Ras-related GTP-binding protein family RGK (Rad-Gem-Kir). It soon appeared that all the members of this family, Gem, Rad, Rem and Rem2, were able to inhibit high-voltage activated Ca2+ channels, thus opening new fields of research to understand the molecular mechanisms leading to channel inhibition and to analyze their potential physiological signification. While much of these works were first concentrated on L-type CaV1.2 channels, it is clear now that presynaptic CaV2.1 and CaV2.2 channels are also sensitive to RGK inhibition. Recent data suggest that multiple routes are used by the RGK proteins to inhibit Ca2+ channels, including modifications of channel targeting and recycling, gating-charge mobility and/or open-channel probability. A direct RGK-CaVβ interaction appears to be absolutely necessary, but additional interactions with the channel protein itself have been highlighted and suggest a finely tuned specificity at the channel level. Whether these interactions also play a role in other channel CaVα or CaVβ functions, such as synaptic transmission or transcriptional regulation, still needs to be investigated.