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bioRxiv · 10.1101/2021.02.01.429206

RIM and RIM-binding protein localize synaptic Cav2 channels in a differential manner to regulate transmission in neuronal circuits

Janosi, B.·Liewald, J. F.·Yu, S.-c.·Umbach, S.·Alcantara, I. C.·Bergs, A. C.·Schneider, M. W.·Shao, J.·Gottschalk, A.
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Abstract

At chemical synapses, voltage-gated Ca2+-channels (VGCCs) translate electrical signals into a trigger for synaptic vesicle (SV) fusion. VGCCs and the Ca2+ microdomains they elicit must be located precisely to primed SVs, to evoke rapid transmitter release. Localization is mediated by Rab3 interacting molecule (RIM) and RIM-binding proteins (RIM-BPs), which interact and bind to the C-terminus of the CaV2 VGCC -subunit. We studied this machinery at the mixed cholinergic/GABAergic neuromuscular junction (NMJ) of Caenorhabditis elegans. rimb-1 mutants had mild synaptic defects, through loosening the anchoring of UNC-2/CaV2 and delaying the onset of SV fusion. UNC-10/RIM deletion much more severely affected transmission. Even though postsynaptic depolarization was reduced, rimb-1 mutants had increased cholinergic (but reduced GABAergic) transmission, to compensate for the delayed release. This did not occur when the excitation-inhibition balance was altered by removing GABA transmission. RIMB-1 thus may differentially regulate transmission in mixed circuits. Untethering the UNC-2/CaV2 channel by removing its C-terminal PDZ ligand exacerbated the rimb-1 defects, and similar phenotypes resulted from acute degradation of the CaV2 {beta}-subunit CCB-1. Therefore, untethering of the CaV2 complex is as severe as its elimination, yet does not abolish transmission, likely due to compensation by CaV1. Thus, robustness and flexibility of synaptic transmission emerges from VGCC regulation.

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Janosi, B., Liewald, J. F., Yu, S.-c., Umbach, S., Alcantara, I. C., Bergs, A. C., Schneider, M. W., Shao, J., Gottschalk, A.. 2021-02-02. RIM and RIM-binding protein localize synaptic Cav2 channels in a differential manner to regulate transmission in neuronal circuits. https://doi.org/10.1101/2021.02.01.429206

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