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Cited by 1,062Neuroscience and Neuropharmacology ResearchCellular transport and secretionExtracellular vesicles in disease

The Presynaptic Active Zone

Open access
Südhof, Thomas C.·2012·Neuron
DOI 10.1016/j.neuron.2012.06.012PMC PMC3743085
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Abstract

Neurotransmitters are released by synaptic vesicle exocytosis at the active zone of a presynaptic nerve terminal. In this review, I discuss the molecular composition and function of the active zone. Active zones are composed of an evolutionarily conserved protein complex containing as core constituents RIM, Munc13, RIM-BP, α-liprin, and ELKS proteins. This complex docks and primes synaptic vesicles for exocytosis, recruits Ca2+ channels to the site of exocytosis, and positions the active zone exactly opposite to post-synaptic specializations via transsynaptic cell-adhesion molecules. Moreover, this complex mediates short- and long-term plasticity in response to bursts of action potentials, thus critically contributing to the computational power of a synapse.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes the molecular composition and function of presynaptic active zones, centered on an evolutionarily conserved core complex of RIM, Munc13, RIM-BP, α-liprin, and ELKS. It argues that this complex docks and primes synaptic vesicles, recruits Ca²⁺ channels, aligns pre- and postsynaptic specializations, and mediates short- and long-term plasticity.

Key findings

  • Active zones are disc-like structures in central vertebrate synapses with a 0.2–0.5 μm diameter, and their core is formed by five conserved proteins: RIM, Munc13, RIM-BP, α-liprin, and ELKS.
  • RIM is a central organizer: its N-terminal zinc finger binds Munc13 and Rab3/Rab27, its PDZ domain binds ELKS and N-/P/Q-type Ca²⁺ channels, and RIM-BPs help tether Ca²⁺ channels to RIM. Loss of the RIM PDZ domain causes selective loss of presynaptic Ca²⁺ channels, a shift to higher Ca²⁺ requirement, and desynchronized release.
  • Munc13 mediates vesicle priming via its MUN domain and regulates short-term plasticity through its C2B, C1, and calmodulin-binding sequences; RIM activates Munc13 by disrupting Munc13 C2A homodimers. RIM1α is required for all presynaptic long-term plasticity analyzed.
  • ELKS is the most enigmatic core protein: deletion of ELKS in C. elegans and ELKS2 in mice did not impair neurotransmitter release, but ELKS2 deletion increased the readily releasable pool; Drosophila bruchpilot deletion decreased release by ~30%. Cryo-EM shows vesicle tethers of 5–20 nm and connectors of ~10 nm, with no dense projections visible.

Methods

  • Review article; no primary experimental data, sample, or new analysis are reported.
  • The paper synthesizes genetic, biochemical, electron microscopy, imaging, and electrophysiological literature, primarily from C. elegans, Drosophila, mice, and vertebrate synapses.
  • Main analysis is conceptual integration of protein–protein interactions and mutant phenotypes into a model of active zone architecture and function.

Limitations

  • Stated: length restrictions preclude discussion of many important papers and issues, and the author apologizes for omissions; much about active zones remains unknown, with open questions noted throughout.
  • Stated/evident: the active zone protein matrix is difficult to purify, and all currently known active zone proteins were identified via antibodies, genetic mutations, or protein–protein interactions.
  • Evident: this is a review without new data; conclusions often rely on invertebrate or knockout models, vertebrate presynaptic α-liprin function is not studied, and EM interpretations remain contested because chemically fixed preparations show dense projections while cryo-EM of unfixed samples does not.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.neuron.2012.06.012

Cites

145 of 145 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

48 of 117 cited sources checked · 20 supported · 2 flagged · accuracy not yet measured

  • Premisecitation

    The central PDZ-domain of RIMs binds N- and P/Q-type but not L-type Ca2+ channels.

    “The central PDZ-domain of RIMs binds at least two proteins: ELKS (Ohtsuka et al., 2002; Wang et al., 2002) and N- and P/Q-type but not L-type Ca2+ channels (Kaeser et al., 2011).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Kaeser et al., 2011 source
  • Interpretationreasoning

    Ca2+ channels are recruited to active zones by a tripartite complex composed of RIMs, RIM-BPs, and the C-terminal tails of the channels.

    “Together, these data suggest that Ca2+ channels are recruited to active zones by a tripartite complex composed of RIMs, RIM-BPs, and the C-terminal tails of the channels (Figure 3).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Kaeser et al., 2011 source
  • Premisecitation

    Piccolo and bassoon are associated with active zones in vertebrates.

    “In addition to these five core active zone proteins, piccolo and bassoon (two large homologous proteins) are associated in vertebrates with active zones (tom Dieck et al., 1998; Wang et al., 1999; Fenster et al., 2000; Limbach et al., 2011), and proteins related to C. elegans SYD-1 are important for the assembly of active zones in invertebrates (Hallam et al., 2002; Patel et al., 2006; Owald et al”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites tom Dieck et al., 1998 source
    • cites Wang et al., 1999 source

      The Abstract describes Bassoon and Piccolo as concentrated at active zones, and the Discussion says Piccolo resembles Bassoon in size and subcellular distribution. But the paper says molecular information about Piccolo was unavailable and does not establish that Piccolo and Bassoon are homologous. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Fenster et al., 2000 source
  • Premisecitation

    Plasma membrane SNARE proteins syntaxin and SNAP-25 and the SM protein Munc18 are not enriched in active zones but distributed all over the plasma membrane.

    “Furthermore, as noted above, the plasma membrane SNARE proteins syntaxin and SNAP-25 and the SM protein Munc18 that are components of the synaptic vesicle fusion machinery for exocytosis (Südhof and Rothman, 2009) are not enriched in active zones but distributed all over the plasma membrane.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Südhof and Rothman, 2009 source
  • Premisecitation

    Ribbon synapses contain their characteristic synaptic ribbons in addition to standard active zones.

    “Ribbon synapses contain their characteristic synaptic ribbons in addition to standard active zones, and the ribbons appear to function as accelerators in the recruitment of vesicles for exocytosis (Matthews and Fuchs, 2010).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Matthews and Fuchs, 2010 source

      The Abstract and Introduction describe synaptic ribbons as structures at the active zones of ribbon synapses. They do not say that ribbon synapses also contain separate, standard active zones; the Abstract instead describes their active zones as specialized. Page numbers were not provided in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • May combine two claims. 38
  • Classified as probably not a substantial claim. 3

  • May combine two claims.

    Premisecitation

    CASK binds in vertebrates but not in invertebrates to α-liprins and to CASKIN.

    “CASK additionally binds in vertebrates but not in invertebrates to α-liprins (Olsen et al., 2005; Wei et al., 2011) and to CASKIN (Tabuchi et al., 2002).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Olsen et al., 2005 source

      The Results section confirms that CASK binds liprin-α2, but the Discussion says the liprin-α–CASK interaction is likely conserved in D. melanogaster and C. elegans—the opposite of the claimed vertebrate-only distinction. Olsen et al. is cited for α-liprins in the citing sentence; CASKIN has a separate citation. Page numbers are not provided in our copy. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites Wei et al., 2011 source
    • cites Tabuchi et al., 2002 source

  • May combine two claims.

    Premisecitation

    In cryo-EM studies of unfixed and unstained synapse preparations, no dense projections are detectable; the only structures visible are the plasma membrane, synaptic vesicles, and sparse filaments that connect vesicles to each other or tether vesicles to the presynaptic plasma membrane.

    “In cryo-EM studies of unfixed and unstained synapse preparations, however, no dense projections are detectable. The only structures visible are the plasma membrane, synaptic vesicles, and sparse filaments that either connect vesicles to each others (“connectors,” average length ~10 nm) or tether vesicles to the presynaptic plasma membrane (“tethers”—5–20 nm; Landis et al., 1988; Fernández-Busnadie”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Landis et al., 1988 source
    • cites Fernández-Busnadiego et al., 2010 source

      Split into 2 atoms — 1 confirmed, 0 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Actin filaments are excluded from the active zone and the vesicle cluster.

    “Besides these proteins, actin was suggested to be an active zone component, but high-resolution electron microscopy (EM) shows that actin filaments are excluded from the active zone and the vesicle cluster (Fernández-Busnadiego et al., 2010).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Fernández-Busnadiego et al., 2010 source

      The Results (Morphology of frozen-hydrated presynaptic terminals; page unavailable) report that actin was only occasionally observed and that long actin bundles induced by OA treatment were generally more than 300 nm from the active zone. The Discussion (Synaptic vesicle distribution in resting synapses is not homogenous; page unavailable) cautions that very short or transient actin filaments could not be detected. The paper therefore supports a low abundance of detectable actin near the active zone, not categorical exclusion from both the active zone and vesicle cluster. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    α-Liprin is required for active zone formation with recruitment of synaptic vesicles and of LAR-type receptor phosphotyrosine phosphatases.

    “Together, these data established that active zone formation with recruitment of synaptic vesicles and of LAR-type receptor phosphotyrosine phosphatases requires α-liprin, possibly by simultaneous binding of α-liprin to the receptor phosphotyrosine phosphatase, RIM, ELKS, Syd-1, and itself.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Dai et al., 2006 source
    • cites Ackley et al., 2005 source

      The Results section, “PTP-3 localization is dependent on nid-1 and syd-2” (page unavailable), supports a role for α-liprin/SYD-2 in recruiting the LAR-type receptor PTP-3 to synapses. The paper also reports altered synaptic-vesicle-marker puncta in syd-2 mutants. But “PTP-3A functions as a molecular linker at synapses” (page unavailable) explicitly says these proteins are required for the size and spacing of synaptic proteins, rather than synapse formation per se; it does not establish that α-liprin is required for active-zone formation or the proposed simultaneous binding. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Taru and Jin, 2011 source

      The Results section (‘LH1 domain is necessary for SYD-2 function in presynaptic assembly’; page unavailable) reports that loss of SYD-2 greatly diminishes synaptic-vesicle and active-zone markers in C. elegans HSN neurons. The Introduction says Liprin-α binds LAR-type receptor phosphatases, but the paper does not establish that Liprin-α is required to recruit those phosphatases to active zones. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The core active zone proteins are not specific for active zones or even neurons.

    “Interestingly, the core active zone proteins are not specific for active zones, or even neurons.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Serra-Pagès et al., 1995 source

      The Results section, “LAR and LIP.1 co-localize to focal adhesions” (page unavailable), reports these proteins at focal adhesions in cultured MCF7 cells, supporting a non-neuronal localization for those proteins. The paper does not identify them as core active-zone proteins or establish that core active-zone proteins generally occur outside active zones or neurons. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The CASK PDZ-domain tightly binds to the C terminus of neurexins, constituting the first example of a "type II" PDZ-domain interaction.

    “CASK was discovered because its PDZ-domain—a component of the MAGUK domains—tightly binds to the C terminus of neurexins, thereby constituting the first example of a “type II” PDZ-domain interaction (Hata et al., 1996).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Hata et al., 1996 source

      The Abstract (page unavailable) reports that CASK was identified through its interaction with neurexins and that binding to neurexin I depends on its C-terminal three residues. The Properties and tissue distribution section (page unavailable) says the interaction is salt-labile and suggests it is weak; it does not establish binding by the PDZ domain specifically or call this the first type II PDZ-domain interaction. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Partial knockout of bassoon causes partial lethality and impairs neurotransmitter release.

    “Partial knockout of bassoon causes partial lethality and impairs neurotransmitter release (Altrock et al., 2003)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Altrock et al., 2003 source

      Figure 1 describes a targeted deletion of part of exon 4 and all of exon 5 in the Bsn gene; the experiments concern homozygous mutants that lack wild-type Bassoon, rather than a clearly defined ‘partial knockout.’ The paper reports fewer actively releasing synapses and reduced evoked responses, supporting impaired neurotransmitter release. No passage found on lethality or survival supports the partial-lethality claim (pages not supplied in our copy). (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Mammalian ELKS genes contain alternative N-terminal promoters and alternatively spliced C-terminal sequences, with a shorter C-terminal sequence that is primarily expressed in brain and a longer C-terminal sequence that is primarily expressed in peripheral tissues.

    “Mammalian ELKS genes contain alternative N-terminal promoters and alternatively spliced C-terminal sequences, with a shorter C-terminal sequence that is primarily expressed in brain and a longer C-terminal sequence that is primarily expressed in peripheral tissues (Wang et al., 2002; Kaeser et al., 2009).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Wang et al., 2002 source
    • cites Kaeser et al., 2009 source

      Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable, 1 not checked. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    A deletion of the 17 C-terminal residues of bruchpilot impaired attachment of synaptic vesicles to t bars in Drosophila synapses and altered synaptic transmission.

    “a deletion of the 17 C-terminal residues of bruchpilot (which are part of the plectin-homology region) impaired attachment of synaptic vesicles to t bars in Drosophila synapses and altered synaptic transmission”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Hallermann et al., 2010 source

      The Results discuss Bassoon-deficient mouse synapses, and the Discussion addresses vesicle tethering by Bassoon, not bruchpilot at Drosophila t bars. Searches for bruchpilot, the 17 C-terminal residues, and the plectin-homology region found no passage in our copy addressing the claimed deletion or its effects. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    RIM-BPs bind to RIMs and to N-, P/Q-, and L-type Ca2+ channels.

    “However, the latter identification may be erroneous since subsequent studies showed that RIM-BPs are highly expressed only in brain and not peripherally and tightly bind to RIM (Wang et al., 2000) and to N-, P/Q-, and L-type Ca2+ channels (Hibino et al., 2002; Kaeser et al., 2011).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Wang et al., 2000 source
    • cites Hibino et al., 2002 source
    • cites Kaeser et al., 2011 source

  • May combine two claims.

    Premisecitation

    Deletion of ELKS in C. elegans and of ELKS2 in mice did not impair neurotransmitter release.

    “deletion of ELKS in C. elegans and of ELKS2 in mice did not impair neurotransmitter release (Deken et al., 2005; Kaeser et al., 2009).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Deken et al., 2005 source
    • cites Kaeser et al., 2009 source

  • May combine two claims.

    Premisecitation

    CASK is composed of an N-terminal CaM kinase-like domain that constitutes a catalytically active, unusual protein kinase, and a C-terminal set of domains characteristic of MAGUKs.

    “CASK is composed of an N-terminal CaM kinase-like domain that constitutes a catalytically active, unusual protein kinase (Mukherjee et al., 2008), and a C-terminal set of domains characteristic of MAGUKs (for membrane-associated guanylate kinases; Hata et al., 1996).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Mukherjee et al., 2008 source
    • cites Hata et al., 1996 source

  • May combine two claims.

    Interpretationcitation

    Piccolo and bassoon are large proteins specific to vertebrates whose major function appears to be to guide synaptic vesicles from the backfield of the synapse to the active zone.

    “Piccolo and bassoon are large proteins specific to vertebrates whose major function appears to be to guide synaptic vesicles from the backfield of the synapse to the active zone (Mukherjee et al., 2010; Hallermann et al., 2010).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Mukherjee et al., 2010 source
    • cites Hallermann et al., 2010 source

      The Introduction describes Bassoon as very large and says Bassoon and Piccolo appear to be vertebrate-specific. The Discussion and Abstract support a role for Bassoon in vesicle supply and reloading, and the Discussion reports impaired vesicle clustering in Bassoon–Piccolo double knockouts. They do not establish that guiding vesicles from the synaptic backfield to the active zone is the major function of both proteins. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Mutations of CASK produce a developmental phenotype in invertebrates, mice, and humans and cause major changes in neuronal function, including a general impairment of synaptic transmission.

    “Mutations of CASK produce a developmental phenotype in invertebrates, mice, and humans (Hoskins et al., 1996; Atasoy et al., 2007; Moog et al., 2011) and cause major changes in neuronal function, including a general impairment of synaptic transmission (Zordan et al., 2005; Atasoy et al., 2007; Sun et al., 2009; Chen and Featherstone, 2011).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Hoskins et al., 1996 source
    • cites Atasoy et al., 2007 source

      The Development of CASK KO Mice section reports a partially penetrant cleft palate, supporting a developmental phenotype in mice. The Spontaneous Neurotransmitter Release section reports altered release-event frequencies, but the evoked-release results found no significant difference from controls. Thus, the paper supports changes in neuronal function, not a general impairment of synaptic transmission. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Moog et al., 2011 source

  • May combine two claims.

    Premisecitation

    P/Q- and N-type Ca2+ channels are localized to active zones, and the related R-type Ca2+ channel may also be present.

    “P/Q- (Cav2.1) and N-type Ca2+ channels (Cav2.2) are localized to active zones, and the related R-type Ca2+ channel (Cav2.3) may also be present (Gasparini et al., 2001; Li et al., 2007).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Gasparini et al., 2001 source

      The introduction states that N- and P/Q-type channels are localized at presynaptic release sites. The Discussion reports evidence favoring R-type channels on the same nerve endings, but it does not establish that R-type channels are at the active zones specifically; it notes that channels may be more or less close to them. Page numbers were not available in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Li et al., 2007

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    In Munc13-1 KO mice synaptic vesicle docking appears to be normal as analyzed by EM of chemically fixed synapses but impaired as analyzed by cryo-EM of unfixed samples.

    “For example, in Munc13-1 KO mice synaptic vesicle docking appears to be normal as analyzed by EM of chemically fixed synapses (Augustin et al., 1999) but impaired as analyzed by cryo-EM of unfixed samples (Siksou et al., 2009).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Augustin et al., 1999 source
    • cites Siksou et al., 2009 source

      The Introduction describes high-pressure freezing combined with electron tomography, and the Results report an almost complete loss of docked vesicles. But the mice studied were Munc13-1/2 double knockouts, not the Munc13-1 knockouts named in the citing sentence. The chemical-fixation finding is attached to a different citation. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    RIM and Munc13 are localized between the dense projections adjacent to the plasma membrane, whereas piccolo and bassoon are more distant and appear to be attached to the tips of the dense projections.

    “Immuno-EM experiments suggested that RIM and Munc13, arguably the two most important active zone proteins, are localized between the dense projections adjacent to the plasma membrane, whereas the cytomatrix proteins piccolo and bassoon are more distant and appear to be attached to the tips of the dense projections (Limbach et al., 2011).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Limbach et al., 2011 source

  • May combine two claims.

    Premisecitation

    CaBP1 increases inactivation of P/Q-type Ca2+ channels, whereas VILIP-2 slows the rate of Ca2+ channel inactivation and enhances facilitation.

    “In addition, another EF-hand Ca2+-binding protein called “calcium-binding protein 1” (CaBP1) increases inactivation of P/Q-type Ca2+ channels (Lee et al., 2002), whereas a third EF-hand Ca2+-binding protein called visinin-like protein 2 (VILIP-2) slows the rate of Ca2+ channel inactivation and enhances facilitation (Lautermilch et al., 2005).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Lee et al., 2002 source
    • cites Lautermilch et al., 2005 source

  • May combine two claims.

    Premisecitation

    Active zones of invertebrate synapses are similar to central vertebrate synapses, except for specializations such as t bars in Drosophila that appear to function in recruiting vesicles to active zones.

    “Active zones of invertebrate synapses are similar to central vertebrate synapses, except for specializations such as the t bars in Drosophila that similar to synaptic ribbons appear to function in recruiting vesicles to active zones (Kittel et al., 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kittel et al., 2006 source

  • May combine two claims.

    Premisecitation

    Deletion of piccolo has no significant effect on survival or on neurotransmitter release in cultured neurons or in acute slices.

    “deletion of piccolo has no significant effect on survival or on neurotransmitter release in cultured neurons or in acute slices (Mukherjee et al., 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mukherjee et al., 2010 source

  • May combine two claims.

    Premisecitation

    Deletion of all large Munc13 isoforms blocks synaptic vesicle exocytosis in autapses formed by hippocampal neurons but produces only a partial impairment of exocytosis in neuromuscular junction synapses.

    “Deletion of all large Munc13 isoforms blocks synaptic vesicle exocytosis in autapses formed by hippocampal neurons but produces only a partial impairment of exocytosis in neuromuscular junction synapses (Varoqueaux et al., 2002, 2005).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Varoqueaux et al., 2002, 2005

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    In the absence of RIM-BP, the organization of the active zone is impaired, and the ultrastructural distribution of the ELKS homolog Bruchpilot at active zones is altered.

    “The Drosophila experiments additionally revealed that in the absence of RIM-BP, the organization of the active zone was impaired, and the ultrastructural distribution of the ELKS homolog Bruchpilot at active zones was altered, suggesting that RIM-BPs may have additional functions besides assisting RIM in the recruitment of Ca2+ channels.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Liu et al., 2011 source
    • The authors state this as an assumption: RIM-BP engages in other interactions besides binding to RIMs and Ca2+ channels.

  • May combine two claims.

    Premisecitation

    ELKS binds to Rab6 in a GTP-dependent manner, implicating it in membrane traffic involving the trans-Golgi complex.

    “It binds to Rab6 in a GTP-dependent manner, implicating it in membrane traffic involving the trans-Golgi complex (Monier et al., 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Monier et al., 2002 source

  • May combine two claims.

    Interpretationreasoning

    Bruchpilot performs a double function in Drosophila synapses, with the N-terminal ELKS component acting like a standard ELKS protein, and the C-terminal plectin-homology region acting in vesicle recruitment analogous to piccolo and bassoon in mammalian synapses.

    “Overall, these studies suggest that bruchpilot performs a double function in Drosophila synapses, with the N-terminal ELKS component acting like a standard ELKS protein, and the C-terminal plectin-homology region acting in vesicle recruitment analogous to piccolo and bassoon in mammalian synapses (see below).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    RIMs contain five identifiable domains: an N-terminal composite domain consisting of a zinc finger surrounded by α helices, a central PDZ domain, two C-terminal C2 domains that do not bind Ca2+, and a conserved proline-rich sequence in the linker between the C2 domains.

    “RIMs (for Rab3-interacting molecules; Wang et al., 1997) contain five identifiable domains (Figure 2): an N-terminal composite domain consisting of a zinc finger surrounded by α helices, a central PDZ domain, two C-terminal C2 domains that different from classical C2 domains do not bind Ca2+, and a conserved proline-rich sequence in the linker sequence between the C2 domains (Wang and Südhof, 2003”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Wang et al., 1997 source
    • cites Wang and Südhof, 2003 source

  • May combine two claims.

    Interpretationreasoning

    ELKS likely functions in several cellular processes and engages in multiple protein-protein interactions.

    “As documented by its repeated rediscovery, ELKS likely functions in several cellular processes, and engages in multiple protein-protein interactions (Figure 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    CB1 receptors for endocannabinoids are excluded from active zones, but enriched in the perisynaptic region.

    “In contrast, CB1 receptors for endocannabinoids are excluded from active zones, but enriched in the perisynaptic region (Nyíri et al., 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nyíri et al., 2005

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    Glutamate acts as an autoinhibitory neurotransmitter at a subset of excitatory synapses, and as a heterosynaptic suppressor of release at some inhibitory synapses.

    “Together, these results describe a novel role for glutamate as an autoinhibitory neurotransmitter at a subset of excitatory synapses, and as a heterosynaptic suppressor of release at some inhibitory synapses, a role that is likely to greatly influence synaptic transmission at these synapses during stimulus trains.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Docking as defined by EM is not a functional definition, and both EM approaches may provide a technique-dependent limited view, with neither allowing the claim of absolute conclusions.

    “The fundamental problem here is that docking as defined by EM is not a functional definition, and both EM approaches may provide a technique-dependent limited view, with neither allowing the claim of absolute conclusions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Many different mechanisms of short-term synaptic plasticity were identified, nearly all of which involve the active zone, although in different ways.

    “Many different mechanisms of short-term synaptic plasticity were identified, nearly all of which involve the active zone, although in different ways.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Chemically fixed preparations reveal an underlying organization of the active zone that is missed in the cryo-EM studies, and the two EM approaches provide complementary insights in the organization of active zones.

    “In that sense, chemically fixed preparations reveal an underlying organization of the active zone that is missed in the cryo-EM studies, and the two EM approaches—EM on chemically fixed and on unfixed preparations—provide complementary insights in the organization of active zones.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Munc13 contains three additional signaling domains that appear to regulate its MUN domain and thereby to mediate short-term plasticity, namely its central C2B domain, C1 domain, and a short Ca2+/calmodulin-binding sequence.

    “However, Munc13 contains three additional signaling domains that appear to regulate its MUN domain and thereby to mediate short-term plasticity, namely its central C2B domain, C1 domain, and a short Ca2+/calmodulin-binding sequence (Figure 5A).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The dense projections observed in chemically fixed preparations would have been seen in cryo-EM images given their size, suggesting that these projections represent the result of chemical fixation.

    “Nevertheless, the dense projections observed in chemically fixed preparations would have been seen in cryo-EM images given their size, suggesting that these projections represent the result of chemical fixation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Munc13 is an active zone protein that is essential for synaptic vesicle priming, probably because it catalyzes SNARE-complex formation via its MUN domain, and that is directly regulated by RIM proteins.

    “As we discussed earlier, Munc13 is an active zone protein that is essential for synaptic vesicle priming, probably because it catalyzes SNARE-complex formation via its MUN domain, and that is directly regulated by RIM proteins.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The central C1 domain of Munc13 binds to diacyl-glycerol as an endogenous ligand and to phorbol esters as a pharmacological activator, and its activation dramatically activates neurotransmitter release.

    “The central C1 domain of Munc13’s binds to diacyl-glycerol as an endogenous ligand and to phorbol esters as a pharmacological activator (Betz et al., 1998), and its activation also dramatically activates neurotransmitter release (Figure 5D; Rhee et al., 2002).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Betz et al., 1998 source
    • cites Rhee et al., 2002 source

  • May combine two claims.

    Premisecitation

    Depolarization-induced suppression of inhibition is a form of short-term plasticity where postsynaptically released endocannabinoids suppress presynaptic release of GABA by inhibiting presynaptic Ca2+ channels.

    “The most prominent example of this process is depolarization-induced suppression of inhibition, a form of short-term plasticity where postsynaptically released endocannabinoids suppress presynaptic release of GABA by inhibiting presynaptic Ca2+ channels (Wilson and Nicoll, 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wilson and Nicoll, 2001 source

  • May combine two claims.

    Interpretationreasoning

    During repeated action potentials, especially at frequencies of >10 Hz, residual Ca2+ accumulates because the decay of Ca2+-transients decelerates as Ca2+-buffers become saturated, resulting in an increase of the release probability and thus facilitation.

    “However, during repeated action potentials, especially at frequencies of >10 Hz, residual Ca2+ accumulates because the decay of Ca2+-transients decelerates as Ca2+-buffers become saturated, resulting in an increase of the release probability and thus facilitation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Presynaptic receptors usually act by inhibiting presynaptic Ca2+ channels and thus represent a major mechanism by which release can be modulated via a uniform pathway that overlaps with other short-term plasticity pathways.

    “Presynaptic receptors usually act by inhibiting presynaptic Ca2+ channels and thus represent a major mechanism by which release can be modulated via a uniform pathway that overlaps with other short-term plasticity pathways.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Presynaptic endocannabinoid CB1 receptors have a major role in short- and long-term plasticity, and presynaptic neuropeptide receptors may additionally mediate short-term plasticity if they are for a neuropeptide that is secreted by the terminal upon prolonged stimulation.

    “However, presynaptic endocannabinoid CB1 receptors also have a major role in short- and long-term plasticity, and presynaptic neuropeptide receptors may additionally mediate short-term plasticity if they are for a neuropeptide that is secreted by the terminal upon prolonged stimulation.”
    Quote in the paperNot a substantial claim
39 of 39

  • The authors state this as an assumption.

    RIM-BP engages in other interactions besides binding to RIMs and Ca2+ channels.

    “can only be explained by the assumption that RIM-BP engages in other interactions besides binding to RIMs and Ca2+ channels.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • PSD-95 nanoclusters concentrate higher density of receptors.

    “as the PSD-95 NCs concentrate higher density of receptors7.”

    From A trans-synaptic nanocolumn aligns neurotransmitter release to receptors (2016) · cites this paper as [7]

    The passages from “Membrane Proteins of Active Zones” discuss receptors concentrated in presynaptic active zones, not receptors concentrated by PSD-95 nanoclusters. Searches for “PSD-95 nanoclusters” and “PSD-95 postsynaptic density receptors clustering” found no passage in our copy addressing the claim. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Cites

Flagged first, then by citations

2 of the 147 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Couteaux, R., and Pecot-Dechavassine, M. (1970). L'Ouverture des vesicules synaptiques au niveau des ‘zones actives.’ Septieme Congres International de Microscopie Electronique (Grenoble, France). pp. 709–710.

Cited by

Sorted by citations

Related

Authors
Südhof, T. C.
Affiliations
Howard Hughes Medical Institute (US)
Corresponding author
Südhof, Thomas C.
ORCID
Südhof, Thomas C.
Venue
Neuron
Publisher
Elsevier BV
Published
2012-07
Volume
75
Issue
1
Pages
11-25
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2012.06.012
PMC
PMC3743085
OpenAlex
W2042920344
Semantic Scholar
6ce5ba42a726cbd7a2cfc4441578765dadd4b913
Cited by
1,062
References
147
Citations by year
2026: 59 · 2025: 79 · 2024: 76 · 2023: 79 · 2022: 85 · 2021: 93 · 2020: 88 · 2019: 78 · 2018: 101 · 2017: 85 · 2016: 61 · 2015: 61 · 2014: 62 · 2013: 47 · 2012: 7
FWCI
21.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion)
  • PubMed Central (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institute of Mental Health (MH086403, MH052804, P50 MH086403, R37-MH052804, R01 MH052804)
  • National Institute of Neurological Disorders and Stroke (R01NS077906, NS077906, P01 NS053862, NS053862)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
Keywords
active zone, synaptic vesicle exocytosis, RIM, Munc13, elk, calcium channels, synaptic plasticity, action potential bursts
MeSH terms
Animals, Exocytosis, Humans, Synaptic Transmission, Neuronal Plasticity, Synaptic Vesicles, Presynaptic Terminals, Neurotransmitter Agents

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-12.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-12.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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