RIM-BPs Mediate Tight Coupling of Action Potentials to Ca 2+ -Triggered Neurotransmitter Release

Abstract

Ultrafast neurotransmitter release requires tight colocalization of voltage-gated Ca(2+) channels with primed, release-ready synaptic vesicles at the presynaptic active zone. RIM-binding proteins (RIM-BPs) are multidomain active zone proteins that bind to RIMs and to Ca(2+) channels. In Drosophila, deletion of RIM-BPs dramatically reduces neurotransmitter release, but little is known about RIM-BP function in mammalian synapses. Here, we generated double conditional knockout mice for RIM-BP1 and RIM-BP2, and analyzed RIM-BP-deficient synapses in cultured hippocampal neurons and the calyx of Held. Surprisingly, we find that in murine synapses, RIM-BPs are not essential for neurotransmitter release as such, but are selectively required for high-fidelity coupling of action potential-induced Ca(2+) influx to Ca(2+)-stimulated synaptic vesicle exocytosis. Deletion of RIM-BPs decelerated action-potential-triggered neurotransmitter release and rendered it unreliable, thereby impairing the fidelity of synaptic transmission. Thus, RIM-BPs ensure optimal organization of the machinery for fast release in mammalian synapses without being a central component of the machinery itself.

RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses

“…The RIM/RIM-BP complex has been implicated in enhancing the efficiency of the fusion machinery and the positioning of synaptic vesicles in close proximity to Ca V s to optimize Ca 2+ -secretion coupling (2,5,6). Recently, Acuna et al (8) showed that deletion of RIM-BP1 and RIM-BP2 in the murine Calyx of Held impairs the reliability of evoked neurotransmitter release, presumably due to an uncoupling of Ca V s from release sites. At the Drosophila NMJ, the RIM-BP ortholog DRBP, together with Bruchpilot, is an AZ core component, and elimination of DRBP causes severe structural deficits in AZ organization, associated with strongly impaired basal transmission and STP (6,7).…”

“…Recently, Acuna et al (8) published a report on the combined loss of RIM-BP1 and RIM-BP2 in mouse synapses. The authors report that although RIM-BPs are not essential for synaptic transmission, AP-triggered neurotransmitter release is more variable and the sensitivity to the Ca 2+ chelator EGTA is increased at the Calyx of Held, suggesting a larger coupling distance of Ca V and the release machinery.…”

Single calcium channels stand out in the crowd

“…release transmitter with low probability. [1][2][3] Here, the number and coupling of VGCCs to synaptic vesicles and the spatio-temporal dynamics of the cytoplasmic cloud of calcium ions following stochastic channel opening has emerged as a key property shaping the presynaptic response after stimulation. In fact, recent evidence has shown that at many fast transmitting presynaptic terminals, only a small number of VGCCs are closely associated with synaptic vesicles via interactions with AZ proteins.…”

“…In fact, recent evidence has shown that at many fast transmitting presynaptic terminals, only a small number of VGCCs are closely associated with synaptic vesicles via interactions with AZ proteins. 2,4,6 At many of these synapses, vesicle release appears to be triggered by the spatially localized and largely nonoverlapping single channel-derived cloud of calcium ions (nanodomain) after channel opening. 1,3,7 In addition, since VGCC open probability during a brief action potential (p 0 ) is often low, vesicle release is unreliable.…”

“…In fact, a recent study has shown that removing RIM binding protein in cultured hippocampal neurons or the calyx of Held, a key component for tethering VGCCs close to synaptic vesicles, leads to a severe loss of these synapses' temporal fidelity. 2 Reliance on nanodomain coupling may also be energetically more efficient since it minimizes the resources required to maintain calcium homeostasis. It is also interesting to consider the role of nanodomain coupling in short-term synaptic plasticity.…”