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Channels (Austin)
2015 Jan 01;95:324-33. doi: 10.1080/19336950.2015.1098793.
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Single calcium channel domain gating of synaptic vesicle fusion at fast synapses; analysis by graphic modeling.
Stanley EF
.
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At fast-transmitting presynaptic terminals Ca(2+) enter through voltage gated calcium channels (CaVs) and bind to a synaptic vesicle (SV) -associated calcium sensor (SV-sensor) to gate fusion and discharge. An open CaV generates a high-concentration plume, or nanodomain of Ca(2+) that dissipates precipitously with distance from the pore. At most fast synapses, such as the frog neuromuscular junction (NMJ), the SV sensors are located sufficiently close to individual CaVs to be gated by single nanodomains. However, at others, such as the mature rodent calyx of Held (calyx of Held), the physiology is more complex with evidence that CaVs that are both close and distant from the SV sensor and it is argued that release is gated primarily by the overlapping Ca(2+) nanodomains from many CaVs. We devised a 'graphic modeling' method to sum Ca(2+) from individual CaVs located at varying distances from the SV-sensor to determine the SV release probability and also the fraction of that probability that can be attributed to single domain gating. This method was applied first to simplified, low and high CaV density model release sites and then to published data on the contrasting frog NMJ and the rodent calyx of Held native synapses. We report 3 main predictions: the SV-sensor is positioned very close to the point at which the SV fuses with the membrane; single domain-release gating predominates even at synapses where the SV abuts a large cluster of CaVs, and even relatively remote CaVs can contribute significantly to single domain-based gating.
Figure 1. The central diagram shows an SV with its sensor 30 nm from the channel pore (vertical yellow dashed line). The concentration of Ca2+ at that distance can be read off the CaV nanodomain profile30 (red line; used in all calculations unless stated; the nanodomain profile with 50 µM fixed buffer, blue line, is shown for comparison). The probability that the SV will fuse, calculated using the equilibrium binding equation (lower left; with 5 independent Ca2+ binding sites each with a 10 µM affinity4) is plotted at the lower right and predicts a release probability of 0.28 (horizontal dashed blue line).
Figure 2. Minimal release site. (A) Calculation of the release probability with a single CaV. The diagram shows a release site with the SV abutting a single CaV with its sensor 10 nm (d) from the channel pore (all diagrams are depicted viewing from the synaptic space, through the surface membrane and into the nerve terminal). The worksheet summarizes the Ca2+ concentration seen by the SV-sensor (Cai); the release probability of an open channel (CaVi, Po); the number of open channels with Po = 0.2 (CaVi * Po), and the overall release probability (PR) calculated as in Fig. 1. The estimated CaV-titration N value (NE) is diagramed on a slider between the minimum possible value, 1, and the maximum value for that synapse (see text). (B) Two CaVs, equidistant from the SV-sensor. Note the PR in the overlapping domain is greater than the sum of the 2 single nanodomains providing an ‘overlap-bonus’ (worksheet not shown). (C) Three CaVs located equidistant from the SV sensor. Worksheet as in A, but with 2 release probabilities: PR, calculated from the pooled Ca2+ (CaV*Cai), and PR-SD the sum of the probabilities that the Cai from each single channel will activate the SV-sensor.
Figure 3. (A) Maximial release site. CaV density up to the 100 nm limit (left diagram) with an added ‘Ca2+ shadow’ due to the SV (right diagram). SVs were arranged in concentric rings at radii (d) centered on the SV-sensor and PR and PR-SD were calculated as above (see adjoining Worksheet). Minor mathematical inconsistencies were introduced by rounding of values. (B) Ca2+ profiles calculated as in Fig. 1 without Ca2+ buffer or in the presence of 10 mM EGTA (as labeled).
Figure 4. (A) Scale diagrams of frog NMJ release sites showing one pair of particle rows (as in freeze-fracture images; a second pair is located on the other side of the mid-line)89 with an adjoining SV with its SV-sensor (assumed initially to be on the leading edge of the SV). The CaV that gates fusion is presumed to be the closest particle38 and is shown with a 23 nm circle (orange dashed line) corresponding to the calculated CaV pore to SV-sensor distance (see text). (B) Based on the structural model in (A) the SV fusion point is predicted to be 43 nm from the CaV pore. (C) Structural model with the corrected SV fusion point at 30 nm from the outer particle row (see text). The SV-sensor was relocated to maintain a CaV pore-to SV sensor distance of 23 nm.
Figure 5. Graphic model of the release sites based on the calyx of Held. A-D. Release site with 6 calcium channels. (A) Channels arranged at various distances from the SV sensor up to 80 nm (see
Fig. 2B for model strategy). The distance from the channel to the SV-sensor is the key factor in the model; thus, the channels could be located at any point on their respective ring, excluding the gray SV shadow region as in the box-bracket example). Worksheet calculation of PR and PR-SD, predicting a low NE value. (B) Summary of data in A. (C) As in A, with 2 CaVs in the inner Ring 1 (one CaV was moved to Ring 1 from Ring 2). (D) As in A, but with no CaVs in the inner Ring 1 (one CaV was moved from Ring 1 to Ring 3). (E) Simulation of release site function at the neonate calyx of Held with all the CaVs located remote from the SV-sensor (Rings 4 and 5). The model predicts a high NE value and high block by EGTA, consistent with experimental findings (Table 1).
Adler,
Alien intracellular calcium chelators attenuate neurotransmitter release at the squid giant synapse.
1991, Pubmed
Adler,
Alien intracellular calcium chelators attenuate neurotransmitter release at the squid giant synapse.
1991,
Pubmed
Augustine,
The calcium signal for transmitter secretion from presynaptic nerve terminals.
1991,
Pubmed
Augustine,
Regulation of transmitter release at the squid giant synapse by presynaptic delayed rectifier potassium current.
1990,
Pubmed
Augustine,
Calcium dependence of presynaptic calcium current and post-synaptic response at the squid giant synapse.
1986,
Pubmed
Baur,
Developmental tightening of cerebellar cortical synaptic influx-release coupling.
2015,
Pubmed
Bennett,
The probability of quantal secretion within an array of calcium channels of an active zone.
2000,
Pubmed
Bertram,
Single-domain/bound calcium hypothesis of transmitter release and facilitation.
1996,
Pubmed
Bertram,
Modeling study of the effects of overlapping Ca2+ microdomains on neurotransmitter release.
1999,
Pubmed
Bollmann,
Control of synaptic strength and timing by the release-site Ca2+ signal.
2005,
Pubmed
Bollmann,
Calcium sensitivity of glutamate release in a calyx-type terminal.
2000,
Pubmed
Borst,
Calcium influx and transmitter release in a fast CNS synapse.
1996,
Pubmed
Branco,
The probability of neurotransmitter release: variability and feedback control at single synapses.
2009,
Pubmed
Brandt,
Few CaV1.3 channels regulate the exocytosis of a synaptic vesicle at the hair cell ribbon synapse.
2005,
Pubmed
Bucurenciu,
Nanodomain coupling between Ca2+ channels and Ca2+ sensors promotes fast and efficient transmitter release at a cortical GABAergic synapse.
2008,
Pubmed
Bucurenciu,
A small number of open Ca2+ channels trigger transmitter release at a central GABAergic synapse.
2010,
Pubmed
Catterall,
Interactions of presynaptic Ca2+ channels and snare proteins in neurotransmitter release.
1999,
Pubmed
Chad,
Calcium domains associated with individual channels can account for anomalous voltage relations of CA-dependent responses.
1984,
Pubmed
Dodge,
Co-operative action a calcium ions in transmitter release at the neuromuscular junction.
1967,
Pubmed
Eggermann,
Nanodomain coupling between Ca²⁺ channels and sensors of exocytosis at fast mammalian synapses.
2011,
Pubmed
Erazo-Fischer,
The role of physiological afferent nerve activity during in vivo maturation of the calyx of Held synapse.
2007,
Pubmed
Fedchyshyn,
Developmental transformation of the release modality at the calyx of Held synapse.
2005,
Pubmed
Fedchyshyn,
Activity-dependent changes in temporal components of neurotransmission at the juvenile mouse calyx of Held synapse.
2007,
Pubmed
Fogelson,
Presynaptic calcium diffusion from various arrays of single channels. Implications for transmitter release and synaptic facilitation.
1985,
Pubmed
Gentile,
A unified model of presynaptic release site gating by calcium channel domains.
2005,
Pubmed
González,
Presynaptic muscarinic receptors reduce synaptic depression and facilitate its recovery at hippocampal GABAergic synapses.
2014,
Pubmed
Harlow,
Dissection of active zones at the neuromuscular junction by EM tomography.
1998,
Pubmed
Harlow,
Alignment of synaptic vesicle macromolecules with the macromolecules in active zone material that direct vesicle docking.
2013,
Pubmed
Haydon,
Localization of individual calcium channels at the release face of a presynaptic nerve terminal.
1994,
Pubmed
Heuser,
Functional changes in frog neuromuscular junctions studied with freeze-fracture.
1974,
Pubmed
Indriati,
Quantitative localization of Cav2.1 (P/Q-type) voltage-dependent calcium channels in Purkinje cells: somatodendritic gradient and distinct somatic coclustering with calcium-activated potassium channels.
2013,
Pubmed
Iwasaki,
Developmental regulation of transmitter release at the calyx of Held in rat auditory brainstem.
2001,
Pubmed
Iwasaki,
Developmental changes in calcium channel types mediating synaptic transmission in rat auditory brainstem.
1998,
Pubmed
Jewett,
Neonatal development of auditory system potentials averaged from the scalp of rat and cat.
1972,
Pubmed
Keller,
An Exclusion Zone for Ca2+ Channels around Docked Vesicles Explains Release Control by Multiple Channels at a CNS Synapse.
2015,
Pubmed
Kim,
Single Ca2+ channels and exocytosis at sensory synapses.
2013,
Pubmed
Kochubey,
Developmental regulation of the intracellular Ca2+ sensitivity of vesicle fusion and Ca2+-secretion coupling at the rat calyx of Held.
2009,
Pubmed
Koike-Tani,
Involvement of AMPA receptor desensitization in short-term synaptic depression at the calyx of Held in developing rats.
2008,
Pubmed
Llinás,
Relationship between presynaptic calcium current and postsynaptic potential in squid giant synapse.
1981,
Pubmed
Llinás,
Transmission by presynaptic spike-like depolarization in the squid giant synapse.
1982,
Pubmed
Luo,
Transmitter release is evoked with low probability predominately by calcium flux through single channel openings at the frog neuromuscular junction.
2015,
Pubmed
Luo,
Single-pixel optical fluctuation analysis of calcium channel function in active zones of motor nerve terminals.
2011,
Pubmed
Luvisetto,
Modal gating of human CaV2.1 (P/Q-type) calcium channels: I. The slow and the fast gating modes and their modulation by beta subunits.
2004,
Pubmed
Matveev,
Ca2+ current versus Ca2+ channel cooperativity of exocytosis.
2009,
Pubmed
Matveev,
Calcium cooperativity of exocytosis as a measure of Ca²+ channel domain overlap.
2011,
Pubmed
Meinrenken,
Local routes revisited: the space and time dependence of the Ca2+ signal for phasic transmitter release at the rat calyx of Held.
2003,
Pubmed
Meinrenken,
Calcium secretion coupling at calyx of Held governed by nonuniform channel-vesicle topography.
2002,
Pubmed
Mochida,
Requirement for the synaptic protein interaction site for reconstitution of synaptic transmission by P/Q-type calcium channels.
2003,
Pubmed
Mulligan,
Mitral cell presynaptic Ca(2+) influx and synaptic transmission in frog amygdala.
2001,
Pubmed
Nagwaney,
Macromolecular connections of active zone material to docked synaptic vesicles and presynaptic membrane at neuromuscular junctions of mouse.
2009,
Pubmed
Nakamura,
Nanoscale distribution of presynaptic Ca(2+) channels and its impact on vesicular release during development.
2015,
Pubmed
Naraghi,
Linearized buffered Ca2+ diffusion in microdomains and its implications for calculation of [Ca2+] at the mouth of a calcium channel.
1997,
Pubmed
Okawa,
Illuminating the multifaceted roles of neurotransmission in shaping neuronal circuitry.
2014,
Pubmed
Pangršič,
EF-hand protein Ca2+ buffers regulate Ca2+ influx and exocytosis in sensory hair cells.
2015,
Pubmed
Parnas,
A theoretical explanation for some effects of calcium on the facilitation of neurotransmitter release.
1980,
Pubmed
Pumplin,
Are the presynaptic membrane particles the calcium channels?
1981,
Pubmed
Ravin,
Simultaneous measurement of evoked release and [Ca2+]i in a crayfish release bouton reveals high affinity of release to Ca2+.
1999,
Pubmed
Robitaille,
Strategic location of calcium channels at transmitter release sites of frog neuromuscular synapses.
1990,
Pubmed
Schmidt,
Nanodomain coupling at an excitatory cortical synapse.
2013,
Pubmed
Schneggenburger,
Ca(2+) channels and transmitter release at the active zone.
2012,
Pubmed
Schneggenburger,
Intracellular calcium dependence of transmitter release rates at a fast central synapse.
2000,
Pubmed
Scimemi,
The number and organization of Ca2+ channels in the active zone shapes neurotransmitter release from Schaffer collateral synapses.
2012,
Pubmed
Shahrezaei,
Ca2+ from one or two channels controls fusion of a single vesicle at the frog neuromuscular junction.
2006,
Pubmed
Shahrezaei,
Consequences of molecular-level Ca2+ channel and synaptic vesicle colocalization for the Ca2+ microdomain and neurotransmitter exocytosis: a monte carlo study.
2004,
Pubmed
Shahrezaei,
Brevity of the Ca2+ microdomain and active zone geometry prevent Ca2+-sensor saturation for neurotransmitter release.
2005,
Pubmed
Sheng,
Physical link and functional coupling of presynaptic calcium channels and the synaptic vesicle docking/fusion machinery.
1998,
Pubmed
Sheng,
Calcium-channel number critically influences synaptic strength and plasticity at the active zone.
2012,
Pubmed
Simon,
Compartmentalization of the submembrane calcium activity during calcium influx and its significance in transmitter release.
1985,
Pubmed
Soldo,
Ca(2+) and frequency dependence of exocytosis in isolated somata of magnocellular supraoptic neurones of the rat hypothalamus.
2004,
Pubmed
Stanley,
Decline in calcium cooperativity as the basis of facilitation at the squid giant synapse.
1986,
Pubmed
Stanley,
Molecular scaffold reorganization at the transmitter release site with vesicle exocytosis or botulinum toxin C1.
2003,
Pubmed
Stanley,
Presynaptic calcium channels and the transmitter release mechanism.
1993,
Pubmed
Stanley,
PresyNaptic calcium channels: why is P selected before N?
2015,
Pubmed
Stanley,
The calcium channel and the organization of the presynaptic transmitter release face.
1997,
Pubmed
Stanley,
Single calcium channels and acetylcholine release at a presynaptic nerve terminal.
1993,
Pubmed
Tarr,
Are unreliable release mechanisms conserved from NMJ to CNS?
2013,
Pubmed
Thomson,
Facilitation, augmentation and potentiation at central synapses.
2000,
Pubmed
Venzin,
Membrane associated particles of the presynaptic active zone in rat spinal cord. A morphometric analysis.
1977,
Pubmed
Vyleta,
Loose coupling between Ca2+ channels and release sensors at a plastic hippocampal synapse.
2014,
Pubmed
Wachman,
Spatial Distribution of Calcium Entry Evoked by Single Action Potentials within the Presynaptic Active Zone.
2004,
Pubmed
Wang,
Synaptic vesicles in mature calyx of Held synapses sense higher nanodomain calcium concentrations during action potential-evoked glutamate release.
2008,
Pubmed
Wang,
Action potential evoked transmitter release in central synapses: insights from the developing calyx of Held.
2009,
Pubmed
Weber,
N-type Ca2+ channels carry the largest current: implications for nanodomains and transmitter release.
2010,
Pubmed
Wong,
Synaptic vesicle capture by CaV2.2 calcium channels.
2013,
Pubmed
Yamashita,
Developmental shift to a mechanism of synaptic vesicle endocytosis requiring nanodomain Ca2+.
2010,
Pubmed
Yang,
Amplitude and kinetics of action potential-evoked Ca2+ current and its efficacy in triggering transmitter release at the developing calyx of Held synapse.
2006,
Pubmed
Yoshikami,
The inhibitory effects of omega-conotoxins on Ca channels and synapses.
1989,
Pubmed
Zucker,
Relationship between transmitter release and presynaptic calcium influx when calcium enters through discrete channels.
1986,
Pubmed
