Rab Interacting Molecules 2 and 3 Directly Interact with the Pore-Forming Ca(V)1.3 Ca(2+) Channel Subunit and Promote Its Membrane Expression

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 C(2)B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α–subunit of Ca(V)1.3 channels (Ca(V)1.3α1), 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 (Ca(V)1.3α1-Ca(V)ß2a) 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 Ca(V)1.3α1-Ca(V)ß2a-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 Ca(V)1.3 Ca(2+) channels and positively regulate their plasma membrane expression in HEK293 cells.