Calcium and Neurotransmitter Release


Information is coded in the brain as patterns of electrical impulses that are transmitted along nerve processes. These impulses are passed from one neuron to the next primarily at chemical synapses where the electrical event is converted to the release of a neurotransmitter substance that activates the next neuron in the pathway. Neurotransmitter release is triggered by the opening of ‘voltage‐sensitive’ calcium channels, the admission of a pulse of Ca2+ ions and the binding of these ions to the neurotransmitter secretion apparatus culminating in the fusion and discharge of a transmitter‐filled secretory vesicle. Increasing evidence suggests that at many synapses an individual release site is gated by ion influx through one or a few nearby calcium channels while at others Ca2+ from many channels summates to drive release. In this section, we explore the physiology of this impulse‐to‐secretion gating mechanism.

Key Concepts

  • Information is transmitted between one neuron and the next at synapses where an upstream (presynaptic) neuron interacts with the membrane of the downstream (postsynaptic) one.
  • Synapses transmit by secreting a chemical neurotransmitter, often across a narrow space (cleft) between pre‐ and postsynaptic surface membranes.
  • Most neurotransmitters are stored in tiny membrane ‘packets’ called synaptic vesicles which can be triggered to secrete by fusing with the presynaptic membrane.
  • The synaptic vesicles are ‘docked’ at the release site ready for secretion which is dependent upon a large local increase in [Ca2+].
  • Transmitter secretion is triggered by an electrical impulse that travels down the presynaptic axon or into a dendrite to release sites.
  • Influx of calcium ions through Ca2+ selective, voltage‐sensitive ion channels links the voltage transient of the action potential to the triggering of secretory vesicle discharge.
  • Ca2+ channels are positioned very close to the secretory vesicles so that when they open the spurt of entering Ca2+ ions, called a ‘calcium domain’, can rapidly and effectively access the triggering sites for synaptic vesicle fusion.

Keywords: presynaptic; calcium channel; transmitter release; ion channel domain; synaptic vesicle; depolarisation; exocytosis

Figure 1. Dependence of release on presynaptic calcium influx. Release is increased when Ca2+ influx is increased but the effectiveness of increased Ca2+ influx depends on how the increase is achieved. At this synapse (crayfish neuromuscular junction) changing the extracellular [Ca2+], which alters the flux per channel, is proportionally more effective than broadening the action potential with a voltage‐dependent K+ channel blocker, which mainly increases the duration of channel openings or the number of channels that open during an action potential. Straight lines correspond to a change in fractional release equal to k[Ca]n, where k is a constant of proportionality, [Ca] is the fractional change in internal [Ca] and n = 5 for resulting from changing external [Ca2+] or 1.6 for action potential broadening. Data adapted from Delaney et al. .
Figure 2. Models of transmitter release site activation by overlapping (a) or single (b) Ca2+ channel domains at the frog neuromuscular junction. At this synapse, the Ca2+ channels form two parallel linear rows and the secretory vesicles are lined up exterior to these rows. The model presumes that the secretory vesicle is docked to a fusion apparatus with multiple Ca2+‐binding sites, four of which must be occupied to initiate fusion. (a) Ca2+ ions enter through a large number of ion channels and pool at the release site to trigger fusion. (b) The opposite extreme model, the fusion apparatus is located sufficiently close to an individual Ca2+ channel so that the Ca2+‐binding sites can be readily occupied by the high concentration of ions in the ‘single‐channel domain’. The approximate extent of a 10 μmol L−1 or higher single‐channel domain is depicted by the blue dashed line.
Figure 3. (a) Nonlinear dependence of release on total Ca2+ influx when extracellular [Ca2+] is reduced and thus the flux per channel at amphibian neuromuscular junction. Changes in Ca2+ influx resulting from a single action potential are estimated by Ca2+‐ sensitive dye. Data plotted on a double logarithmic scale reveal an average slope (i.e. cooperativity) of approximately 4. (b) A much less steep relationship between Ca2+ influx and release is revealed when the junction is exposed to low concentration ω‐CTX that slowly blocks Ca2+ channels over time, thus progressively reducing the number of open channels while not changing the flux per open channel. Log–log slope = 1.7. Data from Shahrezaei et al. .
Figure 4. (a) Freeze‐fracture electron micrograph showing an active zone in an amphibian auditory saccular hair cell characterized by a high density of intramembranous particles. These particles correspond to voltage‐dependent Ca2+ channels and Ca2+‐activated K+ channels. The synaptic vesicles are removed during the freeze‐fracture process since they are attached to the inner membrane leaflet lifted away during cleavage. In an intact active zone, vesicles are localized around these particles (Roberts et al., ). (b) A hypothetical arrangement of synaptic vesicles based on the study of Lenzi et al. . Docked synaptic vesicles, attached to the inner surface of the plasma membrane, are tightly localized to regions containing clusters of Ca2+ channels. Bar, 100 nm. Photomicrograph kindly supplied by R. Jacobs, A.J. Hudspeth and W. Roberts.
Figure 5. Two models depicting essential elements of the calcium channel–transmitter release site protein complex. In model (a), the calcium channel is within 25 nm of the secretory vesicle docking/fusion complex (DF). It was hypothesized that this association requires a protein that links the channel and secretory vesicle docking fusion complex. In effect, this protein serves a double role: to anchor the channel within the active zone and to tether (Tth) the secretory vesicle within the channel calcium domain (dashed line). In model (b) these two functions are depicted as molecular links; an anchor from a ‘base complex’ (BC) that maintains the channel within the active zone, and second by a Tth to the synaptic vesicle (SV) docking/fusion complex (DF). Data from Stanley .


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Further Reading

Homan AE and Meriney SD (2018) Active zone structure‐function relationships at the neuromuscular junction. Synapse 72: e22507.

Llinas RR (1989) Calcium in synaptic transmission. In: Llinas RR (ed.) The Biology of the Brain from Neurons to Networks: Readings from: Scientific American, pp 53–69. Freeman: New York.

Zucker RS (1996) Exocytosis: a molecular and physiological perspective. Neuron 17: 1049–1055.

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Delaney, Kerry R, and Lin, Jen‐We(Jul 2020) Calcium and Neurotransmitter Release. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000027.pub4]