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• W2137890493 abstract "Coupling between voltage-gated Ca2+ influx and synaptic vesicle exocytosis is essential for rapid evoked neurotransmission. Acuna et al. show that the knockout of RIM-BPs, which are key structural components of this coupling, decreases the reliability of evoked neurotransmitter release. Coupling between voltage-gated Ca2+ influx and synaptic vesicle exocytosis is essential for rapid evoked neurotransmission. Acuna et al. show that the knockout of RIM-BPs, which are key structural components of this coupling, decreases the reliability of evoked neurotransmitter release. Rapid chemical synaptic communication in the brain requires synchronous neurotransmitter release triggered by action-potential-triggered Ca2+ influx. This evoked fusion of neurotransmitter-laden synaptic vesicles with the plasma membrane occurs at the presynaptic active zone. The active zone protein scaffold ensures reliable transmission of information encoded in presynaptic action potentials to the postsynaptic neuron (Südhof, 2012Südhof T.C. Neuron. 2012; 75: 11-25Abstract Full Text Full Text PDF PubMed Scopus (646) Google Scholar). This scaffold also serves as a substrate for regulation and plasticity. However, given the reliance of this process on a series of protein-protein interactions, it has been an enduring puzzle as to how the rapid pace of coupling—in the order of 100 μs—between presynaptic action potentials and synaptic vesicle fusion events can be accomplished (Sabatini and Regehr, 1996Sabatini B.L. Regehr W.G. Nature. 1996; 384: 170-172Crossref PubMed Scopus (314) Google Scholar). To achieve rapid synchronous neurotransmission, voltage-gated Ca2+ channels are positioned within nanometers of the sites of synaptic vesicle fusion marked by a complex of active zone proteins (Eggermann et al., 2012Eggermann E. Bucurenciu I. Goswami S.P. Jonas P. Nat. Rev. Neurosci. 2012; 13: 7-21Crossref Scopus (313) Google Scholar). Earlier studies have defined a cascade of interacting proteins that link voltage-gated Ca2+ channels to the site of synaptic vesicle fusion. Among the vast network of active zone proteins, RIM1 and RIM2 have been particularly important as they nucleate a scaffold bridging voltage-gated Ca2+ channels to munc-13—a key component of the release apparatus—as well as to synaptic vesicles via interactions with vesicular proteins such as rab3A (Schoch et al., 2002Schoch S. Castillo P.E. Jo T. Mukherjee K. Geppert M. Wang Y. Schmitz F. Malenka R.C. Südhof T.C. Nature. 2002; 415: 321-326Crossref PubMed Scopus (481) Google Scholar) (Figure 1). Accordingly, loss of RIM1 and RIM2 leads to misalignment of synaptic vesicles and voltage-gated Ca2+ channels as well as a substantial reduction in current flow through presynaptic Ca2+ channels (Kaeser et al., 2011Kaeser P.S. Deng L. Wang Y. Dulubova I. Liu X. Rizo J. Südhof T.C. Cell. 2011; 144: 282-295Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar, Han et al., 2011Han Y. Kaeser P.S. Südhof T.C. Schneggenburger R. Neuron. 2011; 69: 304-316Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar). In this issue of Neuron, Acuna and colleagues examine the function of RIM-binding proteins (RIM-BPs) that are key components of this “RIM scaffold” that couples voltage-gated Ca2+ channels to synaptic vesicle release (Acuna et al., 2015Acuna C. Liu X. Gonzalez A. Südhof T.C. Neuron. 2015; 87 (this issue): 1234-1247Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). In vertebrates, RIM-BPs are encoded by three genes where RIM-BP1 and RIM-BP2 are primarily expressed in brain, while RIM-BP3 largely resides outside of brain (Mittelstaedt and Schoch, 2007Mittelstaedt T. Schoch S. Gene. 2007; 403: 70-79Crossref PubMed Scopus (32) Google Scholar). All RIM-BPs contain an N-terminal and two C-terminal SH3-domains. RIM-BP SH3-domains bind to proline-rich sequences in P/Q-, N-, and L-type voltage-gated Ca2+ channels and to RIMs (Wang et al., 2000Wang Y. Sugita S. Südhof T.C. J. Biol. Chem. 2000; 275: 20033-20044Crossref PubMed Scopus (198) Google Scholar, Hibino et al., 2002Hibino H. Pironkova R. Onwumere O. Vologodskaia M. Hudspeth A.J. Lesage F. Neuron. 2002; 34: 411-423Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, Kaeser et al., 2011Kaeser P.S. Deng L. Wang Y. Dulubova I. Liu X. Rizo J. Südhof T.C. Cell. 2011; 144: 282-295Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar) (Figure 1). In agreement with this premise, in earlier studies, the impairment in presynaptic Ca2+ influx seen in RIM-deficient synapses could only be rescued by expression of RIMs containing the RIM-BP-binding sequence (Kaeser et al., 2011Kaeser P.S. Deng L. Wang Y. Dulubova I. Liu X. Rizo J. Südhof T.C. Cell. 2011; 144: 282-295Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar). This result supported the conclusion that RIM-BP and RIM interaction is important for localizing Ca2+ channels to active zones, but did not exclude a role for other SH3-domain-containing proteins that may also bind to RIMs and regulate Ca2+ channel clustering. In order to directly address the function of RIM-BPs, here, the authors use a genetic approach to delete brain-specific RIM-BPs in hippocampal neurons and in separate experiments at the calyx of Held to investigate their role in neurotransmitter release (Acuna et al., 2015Acuna C. Liu X. Gonzalez A. Südhof T.C. Neuron. 2015; 87 (this issue): 1234-1247Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). A strength of the study is the parallel experiments in small hippocampal synapses—using an optogenetic approach to study unitary synaptic contacts—and in the calyx of Held, a large synapse located at the auditory brainstem, that provides a complementary set of data on how RIM-BPs impact release. The analysis of hippocampal synapses is important as these small synapses constitute the predominant form of synaptic connectivity in the central nervous system. Large synapses such as the calyx of Held, on the other hand, present a biophysically accessible model system to analyze Ca2+ channel fusion coupling by enabling direct electrophysiological assessment of presynaptic Ca2+ channels. The authors probed unitary hippocampal synaptic connections between neurons in paired recordings facilitated by channelrhodopsin2-mediated activation of presynaptic neurons. In this setting, they detected an increase in trial-to-trial variability of neurotransmitter release and an increase in synaptic release failures in RIM-BP-deficient excitatory connections, indicating a decrease in neurotransmitter release probability. RIM-BP1- and RIM-BP2-deficient calyx synapses, on the other hand, showed a significant decrease in the amount of action-potential-induced release and release probability. However, unlike earlier studies on RIM-deficient synapses, at the calyx of Held, loss of RIM-BPs did not lead to alterations in the observable properties of presynaptic Ca2+ channels (Han et al., 2011Han Y. Kaeser P.S. Südhof T.C. Schneggenburger R. Neuron. 2011; 69: 304-316Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar, Kaeser et al., 2011Kaeser P.S. Deng L. Wang Y. Dulubova I. Liu X. Rizo J. Südhof T.C. Cell. 2011; 144: 282-295Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar, Acuna et al., 2015Acuna C. Liu X. Gonzalez A. Südhof T.C. Neuron. 2015; 87 (this issue): 1234-1247Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). The loss of RIM-BPs also did not impact the number of synaptic vesicles ready to be released, so called the “readily releasable pool.” Nevertheless, the release was highly variable in hippocampal synapses, consistent with an increase in release failures potentially due to a larger distance of Ca2+ channels to sites of vesicle fusion. In agreement with this premise, the release at RIM-BP-deficient synapses was more sensitive to the slow Ca2+-buffer EGTA than release at wild-type synapses, suggesting that the distance that incoming Ca2+ ions need to traverse to elicit vesicle fusion is longer. Taken together, the results from both systems are consistent with the interpretation that RIM-BPs regulate efficient coupling between voltage-gated Ca2+ channels and synaptic vesicles within the readily releasable pool without affecting the properties of Ca2+ influx at the presynaptic terminal. The authors also demonstrated that this uncoupling between voltage-gated Ca2+ channels and synaptic vesicle fusion events in RIM-BP-deficient synapses had a profound impact on neurotransmission fidelity during high-frequency spike trains measured in calyx synapses. The current results agree with earlier biochemical studies on the interactions of RIM-BPs with RIMs and voltage-gated Ca2+ channels (Wang et al., 2000Wang Y. Sugita S. Südhof T.C. J. Biol. Chem. 2000; 275: 20033-20044Crossref PubMed Scopus (198) Google Scholar, Hibino et al., 2002Hibino H. Pironkova R. Onwumere O. Vologodskaia M. Hudspeth A.J. Lesage F. Neuron. 2002; 34: 411-423Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, Kaeser et al., 2011Kaeser P.S. Deng L. Wang Y. Dulubova I. Liu X. Rizo J. Südhof T.C. Cell. 2011; 144: 282-295Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar). RIM-BPs appear to connect Ca2+ channels to the active zone in partnership with RIMs, which also directly bind to Ca2+ channels (Kaeser et al., 2011Kaeser P.S. Deng L. Wang Y. Dulubova I. Liu X. Rizo J. Südhof T.C. Cell. 2011; 144: 282-295Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar). However, RIM- and RIM-BP-deficient synapses differ significantly with respect to their Ca2+ influx phenotype. RIM-deficient synapses exhibit a substantial loss of Ca2+ channels from presynaptic terminals (Kaeser et al., 2011Kaeser P.S. Deng L. Wang Y. Dulubova I. Liu X. Rizo J. Südhof T.C. Cell. 2011; 144: 282-295Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar) and a decrease in overall presynaptic Ca2+ influx (Han et al., 2011Han Y. Kaeser P.S. Südhof T.C. Schneggenburger R. Neuron. 2011; 69: 304-316Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar, Kaeser et al., 2011Kaeser P.S. Deng L. Wang Y. Dulubova I. Liu X. Rizo J. Südhof T.C. Cell. 2011; 144: 282-295Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar), whereas in RIM-BP-deficient synapses presynaptic Ca2+ currents remain unaffected. This phenotypic difference suggests that RIMs perform a core function in recruiting Ca2+ channels and RIM-BPs to the active zone. A central role for RIMs in active zone assembly is also consistent with the finding that loss of RIMs alter spontaneous release (Kaeser et al., 2012Kaeser P.S. Deng L. Fan M. Südhof T.C. Proc. Natl. Acad. Sci. USA. 2012; 109: 11830-11835Crossref PubMed Scopus (79) Google Scholar), but RIM-BP deficient synapses have largely intact spontaneous release properties (Acuna et al., 2015Acuna C. Liu X. Gonzalez A. Südhof T.C. Neuron. 2015; 87 (this issue): 1234-1247Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). The relative impact of RIM versus RIM-BP loss-of-function also varies in different organisms despite their evolutionary conservation. The deletion of RIM-BP at the Drosophila neuromuscular junction results in a more substantive phenotype that influences coupling of vesicles to Ca2+ influx as well as deficiencies in the properties of the readily releasable synaptic vesicle pool (Müller et al., 2015Müller M. Genç Ö. Davis G.W. Neuron. 2015; 85: 1056-1069Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). Comparison of RIM and RIM-BP loss-of-function phenotypes in mouse and Drosophila synapses suggests that, in mammals, RIM proteins are dominant in nucleating functional active zones, whereas RIM-BPs play a regulatory role (Schoch et al., 2002Schoch S. Castillo P.E. Jo T. Mukherjee K. Geppert M. Wang Y. Schmitz F. Malenka R.C. Südhof T.C. Nature. 2002; 415: 321-326Crossref PubMed Scopus (481) Google Scholar, Kaeser et al., 2011Kaeser P.S. Deng L. Wang Y. Dulubova I. Liu X. Rizo J. Südhof T.C. Cell. 2011; 144: 282-295Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar, Acuna et al., 2015Acuna C. Liu X. Gonzalez A. Südhof T.C. Neuron. 2015; 87 (this issue): 1234-1247Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). In contrast, in Drosophila RIM-BPs appear to be essential for proper organization of the active zone, whereas RIMs play a lesser role (Liu et al., 2011Liu K.S. Siebert M. Mertel S. Knoche E. Wegener S. Wichmann C. Matkovic T. Muhammad K. Depner H. Mettke C. et al.Science. 2011; 334: 1565-1569Crossref PubMed Scopus (201) Google Scholar, Müller et al., 2015Müller M. Genç Ö. Davis G.W. Neuron. 2015; 85: 1056-1069Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). The current study by Acuna et al., 2015Acuna C. Liu X. Gonzalez A. Südhof T.C. Neuron. 2015; 87 (this issue): 1234-1247Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar provides new insight into the role of RIM-BPs in neurotransmitter release in ensuring accurate information transfer in mammalian central neuronal circuits. The finding that loss of RIM-BPs substantially impairs the reliability of synaptic transmission during activity advances our understanding of the role of these proteins in synaptic transmission. These findings, when taken together with the identification of RIM-BP1 mutations associated with certain neuropsychiatric disorders (Acuna et al., 2015Acuna C. Liu X. Gonzalez A. Südhof T.C. Neuron. 2015; 87 (this issue): 1234-1247Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar), suggests a key role for the precision of rapid information transfer at synaptic circuits in the pathophysiology of brain disorders. Given their critical role in Ca2+ influx-fusion coupling, RIM-BPs may provide a target for signaling cascades and a key substrate for synaptic plasticity, as even subtle alterations in voltage-gated Ca2+ channel-fusion coupling can have profound effects on the efficacy of neurotransmitter release (Vyleta and Jonas, 2014Vyleta N.P. Jonas P. Science. 2014; 343: 665-670Crossref PubMed Scopus (122) Google Scholar). Therefore, it is plausible to expect that RIM-BPs may mediate presynaptic forms of long-term synaptic plasticity. Active zone proteins ensure precise localization of synaptic vesicles and voltage-gated Ca2+ channels for rapid release but are also critical for other forms of release, likely organizing release into functionally distinct domains. Interestingly, unlike munc-13 and RIMs (Südhof, 2012Südhof T.C. Neuron. 2012; 75: 11-25Abstract Full Text Full Text PDF PubMed Scopus (646) Google Scholar, Kaeser et al., 2012Kaeser P.S. Deng L. Fan M. Südhof T.C. Proc. Natl. Acad. Sci. USA. 2012; 109: 11830-11835Crossref PubMed Scopus (79) Google Scholar), loss of RIM-BPs does not alter spontaneous release (in small hippocampal synapses as well as in the calyx of Held) (Acuna et al., 2015Acuna C. Liu X. Gonzalez A. Südhof T.C. Neuron. 2015; 87 (this issue): 1234-1247Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). In contrast to synchronous neurotransmitter release, the spontaneous release process is independent of the timing precision of presynaptic action potentials, as it carries out neuromodulatory and neuronal signaling functions without being directly involved in information transfer (Kavalali, 2015Kavalali E.T. Nat. Rev. Neurosci. 2015; 16: 5-16Crossref PubMed Scopus (271) Google Scholar). This key difference highlights a selective role for RIM-BPs among active zone proteins in the regulation of evoked release without impacting spontaneous neurotransmission. The current data suggest that the interaction of RIM-BPs with voltage-gated Ca2+ channels isolates the regulation of evoked release from spontaneous fusion. However, there is growing evidence that spontaneous release events may also be regulated by voltage-gated Ca2+ influx, suggesting that other active zone proteins may act as the main substrate for Ca2+-dependent regulation of spontaneous release (Kavalali, 2015Kavalali E.T. Nat. Rev. Neurosci. 2015; 16: 5-16Crossref PubMed Scopus (271) Google Scholar). In sum, the study by Acuna et al., 2015Acuna C. Liu X. Gonzalez A. Südhof T.C. Neuron. 2015; 87 (this issue): 1234-1247Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar provides a new perspective on the emerging picture that single active zones not only form structural scaffolds but also function as versatile platforms that organize time-dependent properties of neurotransmitter release and render distinct forms of neurotransmitter release susceptible to selective plasticity. RIM-BPs Mediate Tight Coupling of Action Potentials to Ca2+-Triggered Neurotransmitter ReleaseAcuna et al.NeuronSeptember 23, 2015In BriefAcuna et al. show that active zone proteins called RIM-BPs are not essential for neurotransmitter release as such, but are required for tight coupling of presynaptic Ca2+ channels to the release machinery. As a result, deletion of RIM-BPs impairs the reliability and fidelity of synaptic transmission in response to action potentials. Full-Text PDF Open Archive" @default.
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• W2137890493 title "How Do RIM-BPs Link Voltage-Gated Ca 2+ Channels to Evoked Neurotransmitter Release?" @default.
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