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  • Review Article
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Presynaptic ionotropic receptors and control of transmitter release

Key Points

  • Neurotransmission at many central synapses can be regulated by various presynaptic ionotropic receptors. The regulatory mechanism depends on the properties of the receptor, as well as on the characteristics of the specific synapse.

  • Anionic and Ca2+-impermeable cationic receptors modulate release by affecting the presynaptic membrane potential. They can shunt action potential propagation to inhibit release, or bring membrane potential closer to threshold to enhance release.

  • Ca2+-permeable receptors can modulate release by altering the intraterminal concentration of Ca2+. They can do so in three different ways: by bringing membrane potential closer to the activation threshold of Ca2+ channels, by directly allowing Ca2+ entry, and by promoting Ca2+-dependent Ca2+ release from internal pools.

  • Not all the actions of presynaptic ionotropic receptors depend directly on ion flow. Kainate and NMDA (N-methyl-D-aspartate) receptors can modulate release through a metabotropic effect and through the production of nitric oxide, respectively.

  • There are several possible sources of endogenous agonist to activate presynaptic ionotropic receptors. They include glia, dendrites and axons. In addition, axonal release can act on presynaptic receptors present in a neighbouring synapse or on autoreceptors to modulate its own release.

  • To be more informative, future studies of presynaptic modulation should aim to take into account the physiological context in which such a modulation might take place.

Abstract

Presynaptic nerve terminals are dynamic structures that release vesicular packages of neurotransmitter, affecting the activity of postsynaptic cells. This release of transmitter occurs both spontaneously and after the arrival of an action potential at presynaptic terminals. How is the release process modulated? Although ionotropic receptors are commonly regarded as postsynaptic elements that mediate the effect of the released chemical signals, a wide variety of ionotropic receptors have also been found on presynaptic membranes near release sites, where they powerfully influence vesicle fusion. Here, we provide an overview of the presynaptic ionotropic receptors that modulate transmitter release, focusing on their proposed mechanisms of action.

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Figure 1: Presynaptic factors that influence transmitter release.
Figure 2: Presynaptic inhibition in the spinal cord.
Figure 3: Concentration-dependent effect of agonist on transmitter release.
Figure 4: Presynaptic inhibition and AMPA receptors.
Figure 5: Target-dependent effects of autoreceptors.

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Acknowledgements

Our work has been supported by the Christopher Reeves Paralysis Foundation and the National Institutes of Health.

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Correspondence to Amy B. MacDermott.

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DATABASES

LocusLink

AMPA receptors

GABA receptors

Glycine receptors

Kainate receptors

nACh receptors

TRPV1

NMDA receptors

P2X receptors

FURTHER INFORMATION

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Glossary

SHUNTING

A phenomenon by which membrane depolarization that is induced by a given current is attenuated because of an enhanced membrane conductance.

INPUT RESISTANCE

The voltage change elicited by the injection of current into a cell, divided by the amount of current injected.

EVOKED POSTSYNAPTIC CURRENTS

Synaptic currents that are elicited by firing an action potential in a population of axons. They commonly reflect release from many presynaptic fibres, although it is possible to study release from one or a few fibres using so-called minimal stimulation protocols.

QUANTAL ANALYSIS

This type of analysis aims to describe release as a function of three basic parameters: the number of release sites (n), the probability of release at each site (p), and the postsynaptic response elicited by a single transmitter vesicle (q). The amplitude of a synaptic event can be described by the product npq.

TRANSMISSION FAILURES

Cases in which a presynaptic action potential fails to produce a postsynaptic response.

MINIATURE POSTSYNAPTIC CURRENTS

Currents that are observed in the absence of presynaptic action potentials, thought to correspond to the response that are elicited by a single vesicle of transmitter. Changes in their frequency are indicative of presynaptic modifications, whereas changes in their amplitude are often interpreted as alterations of postsynaptic responsiveness to the transmitter.

PERFORATED PATCH CLAMP

Variation on the patch-clamp technique in which it is not necessary to break the cell membrane to gain access to the cytoplasm of the cell to control its voltage. Instead, the recording pipette contains a molecule that can perforate the membrane (often an antibiotic), generating pores through which cations can flow.

STEADY-STATE CURRENT

The residual current that is observed after a given receptor has become desensitized or fully activated.

SPONTANEOUS POSTSYNAPTIC CURRENTS

Currents that are observed in the absence of evoked action potentials. However, spontaneous currents are distinct from miniature currents in that they are sensitive to Na+ channel blockers such as tetrodotoxin.

CLIMBING FIBRES

Cerebellar afferents that arise from the inferior olivary nucleus, each of which forms multiple synapses with a single Purkinje cell.

PAIRED-PULSE FACILITATION

If two stimuli are delivered to an axon in close succession, the postsynaptic response to the second stimulus is often larger than to the first one. This phenomenon is referred to as paired-pulse facilitation, and is thought to depend on the accumulation of Ca2+ that ensues after successive stimuli.

MOSSY FIBRES

Axons of hippocampal granule cells, which form synapses with CA3 pyramidal neurons. Mossy fibre terminals are among the largest in the central nervous system.

LONG-TERM POTENTIATION

(LTP). An enduring increase in the amplitude of excitatory postsynaptic potentials as a result of high-frequency (tetanic) stimulation of afferent pathways. It is measured both as the amplitude of excitatory postsynaptic potentials and as the magnitude of the postsynaptic-cell population spike. LTP is most often studied in the hippocampus, and is often considered to be the cellular basis of learning and memory in vertebrates.

PRESYNAPTIC VOLLEY

The wave of a synaptic potential with the shortest latency. It is proportional to the number of active presynaptic fibres, and its amplitude serves to estimate the strength of an afferent input.

UNITARY POSTSYNAPTIC CURRENTS

Currents that result from the activation of a single presynaptic fibre. They often require that the pre- and postsynaptic cells be recorded simultaneously to ensure that the postsynaptic response occurs as a result of an action potential in the presynaptic cell.

PENTRAXIN

(or Pentaxin). Protein of discoid appearance under the electron microscope, consisting of five non-covalently bound subunits.

PDZ DOMAIN

A peptide-binding domain that is important for the organization of membrane proteins, particularly at cell–cell junctions, including synapses. It can bind to the carboxyl termini of proteins or can form dimers with other PDZ domains. PDZ domains are named after the proteins in which these sequence motifs were originally identified (PSD95, Discs large, zona occludens 1).

PERTUSSIS TOXIN

The causative agent of whooping cough, pertussis toxin causes the persistent activation of Gi proteins by catalysing the ADP-ribosylation of the α-subunit.

PARALLEL FIBRES

The axons of cerebellar granule cells. Parallel fibres emerge from the molecular layer of the cerebellar cortex towards the periphery, where they extend branches perpendicular to the main axis of Purkinje neurons and form so-called en passant synapses with this cell type.

LONG-TERM DEPRESSION

(LTD). An enduring weakening of synaptic strength that is thought to interact with long term potentiation (LTP) as cellular mechanisms of learning and memory in structures such as the hippocampus and cerebellum.

SCHAFFER COLLATERALS

Axons of the CA3 pyramidal cells of the hippocampus that form synapses with the apical dendrites of CA1 neurons.

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Engelman, H., MacDermott, A. Presynaptic ionotropic receptors and control of transmitter release. Nat Rev Neurosci 5, 135–145 (2004). https://doi.org/10.1038/nrn1297

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