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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).
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