Rab Interacting Molecules 2 and 3 Directly Interact with the Pore-Forming CaV1.3 Ca2+ Channel Subunit and Promote Its Membrane Expression

Maria M. Picher, Ana-Maria Oprişoreanu, SangYong Jung, Katrin Michel, Susanne Schoch, Tobias Moser

Rab interacting molecules (RIMs) are multi-domain proteins that positively regulate the number of Ca(2+) channels at the presynaptic active zone (AZ). Several molecular mechanisms have been demonstrated for RIM-binding to components of the presynaptic Ca(2+) channel complex, the key signaling element at the AZ. Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α-subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). Co-expressing full-length RIM2α with a Ca(2+) channel complex closely resembling that of IHCs (CaV1.3α1-CaVß2a) in HEK293 cells doubled the Ca(2+)-current and shifted the voltage-dependence of Ca(2+) channel activation by approximately +3 mV. Co-expression of the short RIM isoform RIM3γ increased the CaV1.3α1-CaVß2a-mediated Ca(2+)-influx in HEK293 cells, but disruption of RIM3γ in mice left Ca(2+)-influx in IHCs and hearing intact. In conclusion, we propose that RIM2α and RIM3γ directly interact with the C-terminus of the pore-forming subunit of CaV1.3 Ca(2+) channels and positively regulate their plasma membrane expression in HEK293 cells.