| First Author | Hirano M | Year | 2017 |
| Journal | J Biol Chem | Volume | 292 |
| Issue | 22 | Pages | 9365-9381 |
| PubMed ID | 28377503 | Mgi Jnum | J:243671 |
| Mgi Id | MGI:5909370 | Doi | 10.1074/jbc.M117.778829 |
| Citation | Hirano M, et al. (2017) C-terminal splice variants of P/Q-type Ca2+ channel CaV2.1 alpha1 subunits are differentially regulated by Rab3-interacting molecule proteins. J Biol Chem 292(22):9365-9381 |
| abstractText | Voltage-dependent Ca2+ channels (VDCCs) mediate neurotransmitter release controlled by presynaptic proteins such as the scaffolding proteins Rab3-interacting molecules (RIMs). RIMs confer sustained activity and anchoring of synaptic vesicles to the VDCCs. Multiple sites on the VDCC alpha1 and beta subunits have been reported to mediate the RIMs-VDCC interaction, but their significance is unclear. Because alternative splicing of exons 44 and 47 in the P/Q-type VDCC alpha1 subunit CaV2.1 gene generates major variants of the CaV2.1 C-terminal region, known for associating with presynaptic proteins, we focused here on the protein regions encoded by these two exons. Co-immunoprecipitation experiments indicated that the C-terminal domain (CTD) encoded by CaV2.1 exons 40-47 interacts with the alpha-RIMs, RIM1alpha and RIM2alpha, and this interaction was abolished by alternative splicing that deletes the protein regions encoded by exons 44 and 47. Electrophysiological characterization of VDCC currents revealed that the suppressive effect of RIM2alpha on voltage-dependent inactivation (VDI) was stronger than that of RIM1alpha for the CaV2.1 variant containing the region encoded by exons 44 and 47. Importantly, in the CaV2.1 variant in which exons 44 and 47 were deleted, strong RIM2alpha-mediated VDI suppression was attenuated to a level comparable with that of RIM1alpha-mediated VDI suppression, which was unaffected by the exclusion of exons 44 and 47. Studies of deletion mutants of the exon 47 region identified 17 amino acid residues on the C-terminal side of a polyglutamine stretch as being essential for the potentiated VDI suppression characteristic of RIM2alpha. These results suggest that the interactions of the CaV2.1 CTD with RIMs enable CaV2.1 proteins to distinguish alpha-RIM isoforms in VDI suppression of P/Q-type VDCC currents. |
