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

doi:10.3389/fncel.2017.00160

Rab Interacting Molecules 2 and 3 Directly Interact with the Pore-Forming Ca_V1.3 Ca²⁺ Channel Subunit and Promote Its Membrane Expression

Front Cell Neurosci. 2017 Jun 8:11:160. doi: 10.3389/fncel.2017.00160. eCollection 2017.

Authors

Maria M Picher^{1

2

3}, Ana-Maria Oprişoreanu⁴, SangYong Jung^{1

2

5}, Katrin Michel⁴, Susanne Schoch⁴, Tobias Moser^{1

2

3

6}

Affiliations

¹ Institute for Auditory Neuroscience and InnerEarLab, University Medical Center GöttingenGöttingen, Germany.
² Synaptic Nanophysiology Group, Max Planck Institute for Biophysical ChemistryGöttingen, Germany.
³ Göttingen Graduate School for Neurosciences and Molecular Biosciences, University of GöttingenGöttingen, Germany.
⁴ Institute of Neuropathology and Department of Epileptology, University of BonnBonn, Germany.
⁵ Neuro Modulation and Neuro Circuitry Group, Singapore Bioimaging Consortium (SBIC), Biomedical Sciences InstitutesSingapore, Singapore.
⁶ Collaborative Research Center 889, University of GöttingenGöttingen, Germany.

Abstract

Rab interacting molecules (RIMs) are multi-domain proteins that positively regulate the number of Ca²⁺ channels at the presynaptic active zone (AZ). Several molecular mechanisms have been demonstrated for RIM-binding to components of the presynaptic Ca²⁺ 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 Ca_V1.3 channels (Ca_V1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). Co-expressing full-length RIM2α with a Ca²⁺ channel complex closely resembling that of IHCs (Ca_V1.3α1-Ca_Vß2a) in HEK293 cells doubled the Ca²⁺-current and shifted the voltage-dependence of Ca²⁺ channel activation by approximately +3 mV. Co-expression of the short RIM isoform RIM3γ increased the Ca_V1.3α1-Ca_Vß2a-mediated Ca²⁺-influx in HEK293 cells, but disruption of RIM3γ in mice left Ca²⁺-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_V1.3 Ca²⁺ channels and positively regulate their plasma membrane expression in HEK293 cells.

Keywords: active zone; channel clustering; exocytosis; hair cell; hearing; ribbon synapse.