RIM‐binding proteins recruit BK‐channels to presynaptic release sites adjacent to voltage‐gated Ca2+‐channels. (2nd July 2018)

• Record Type: Journal Article
• Authors: Sclip, Alessandra; Acuna, Claudio; Luo, Fujun; Südhof, Thomas C
• Is Part Of: EMBO journal. Volume 37:Number 16(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-07-02
• Subjects: active zone -- BK‐channels -- nano‐domain coupling -- neurotransmitter release -- voltage‐gated calcium channels; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201798637
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: The active zone of presynaptic nerve terminals organizes the neurotransmitter release machinery, thereby enabling fast Ca 2+ ‐triggered synaptic vesicle exocytosis. BK‐channels are Ca 2+ ‐activated large‐conductance K + ‐channels that require close proximity to Ca 2+ ‐channels for activation and control Ca 2+ ‐triggered neurotransmitter release by accelerating membrane repolarization during action potential firing. How BK‐channels are recruited to presynaptic Ca 2+ ‐channels, however, is unknown. Here, we show that RBPs (for RIM‐binding proteins), which are evolutionarily conserved active zone proteins containing SH3‐ and FN3‐domains, directly bind to BK‐channels. We find that RBPs interact with RIMs and Ca 2+ ‐channels via their SH3‐domains, but to BK‐channels via their FN3‐domains. Deletion of RBPs in calyx of Held synapses decreased and decelerated presynaptic BK‐currents and depleted BK‐channels from active zones. Our data suggest that RBPs recruit BK‐channels into a RIM‐based macromolecular active zone complex that includes Ca 2+ ‐channels, synaptic vesicles, and the membrane fusion machinery, thereby enabling tight spatio‐temporal coupling of Ca 2+ ‐influx to Ca 2+ ‐triggered neurotransmitter release in a presynaptic terminal. Synopsis: Direct interaction between large‐conductance potassium BK‐channels and scaffold RIM‐binding proteins (RBPs) in the nerve presynaptic terminal is required for recruitment of BKα to active zone Ca 2+ ‐channels and efficient control of neurotransmitter release. Multi‐domain protein RBP2 and BKα‐channels directly interact in vitro as well as in mouse brain homogenates. RBP FN3‐domains bind to both RCK‐domains of BKα‐channels. Expression of RBP2 shifts the voltage‐dependence of BKα‐channels in HEK293T cells and deletion of RBPs decreases presynaptic BK‐currents. RBP1, 2 double knockout mice show impaired presynaptic localization of BKα‐channel protein. Abstract : RIM‐binding proteins ensure coupling of BK‐channels to Ca 2+ channels in the active zone to control neurotransmitter release.