title: Rim1 modulates direct G-protein regulation of Ca(v)2.2 channels.
abstract: Regulation of presynaptic voltage-gated calcium channels is critical for depolarization-evoked neurotransmitter release. Various studies attempted to determine the functional implication of Rim1, a component of the vesicle release machinery. Besides to couple voltage-gated Ca(2+) channels to the presynaptic vesicle release machinery, it was evidenced that Rim1 also prevents voltage-dependent inactivation of the channels through a direct interaction with the ancillary β-subunits, thus facilitating neurotransmitter release. However, facilitation of synaptic activity may also be caused by a reduction of the inhibitory pathway carried by G-protein-coupled receptors. Here, we explored the functional implication of Rim1 in G-protein regulation of Ca(v)2.2 channels. Activation of μ-opioid receptors expressed in HEK-293 cells along with Ca(v)2.2 channels produced a drastic current inhibition both in control and Rim1-expressing cells. In contrast, Rim1 considerably promoted the extent of current deinhibition following channel activation, favoring sustained Ca(2+) influx under prolonged activity. Our data suggest that Rim1-induced facilitation of neurotransmitter release may come as a consequence of a decrease in the inhibitory pathway carried by G-proteins that contributes, together with the slowing of channel inactivation, to maintain Ca(2+) influx under prolonged activity. The present study also furthers functional insights in the importance of proteins from the presynaptic vesicle complex in the regulation of voltage-gated Ca(2+) channels by G-proteins.
authors.affiliation: Laboratory of Ion Channels, Functions and Pathologies, Grenoble Institute of Neurosciences, INSERM U836, Grenoble, France. norbert.weiss@yahoo.fr
authors.forename: Norbert
authors.initials: N
authors.lastname: Weiss
authors.forename: Alejandro
authors.initials: A
authors.lastname: Sandoval
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kyonaka
authors.forename: Ricardo
authors.initials: R
authors.lastname: Felix
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.forename: Michel
authors.initials: M
authors.lastname: De Waard
mesh_terms: D020864:Calcium Channels, N-Type / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D009419:Nerve Tissue Proteins / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000378:metabolism
chemical_list: C500545:CACNA1B protein, human; D020864:Calcium Channels, N-Type; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; C491492:RIMS1 protein, human; D019204:GTP-Binding Proteins