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Roles and rules of kainate receptors in synaptic transmission

Nature Reviews Neuroscience volume 4, pages 481–495 (2003)Cite this article

Key Points

  • Kainate receptors are a class of ionotropic glutamate receptors with remarkable structural diversity. There are five different subunits, some of which are susceptible to alternative splicing and mRNA editing. Pharmacologically, they are difficult to distinguish from other glutamate receptors, such as the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) type, but important progress has been made in identifying several relatively selective agonists and antagonists.

  • Kainate receptors have pre- and postsynaptic distributions. Postsynaptic kainate receptors contribute to synaptic transmission, and the slow time-course of their response endows synapses with longer integration times. Presynaptically, kainate receptors modulate transmitter release from excitatory and inhibitory synapses in different brain regions. The presynaptic mechanisms whereby kainate receptors modulate excitation and inhibition are quite complex and remain a matter of debate.

  • Kainate receptors are also involved in synaptic plasticity during development and in the adult, but their mechanism of action remains to be elucidated. Similarly, the long-held view that kainate receptors are relevant to the generation of epilepsy is a matter of debate, as there is contradictory evidence on their role as pro- or anticonvulsant molecules.

  • In addition to these debates in the field, two additional observations make kainate receptors one of the most intriguing receptor family in the nervous system. First, although there are several kainate receptor-knockout animals, they have not been particularly informative about the function of these receptors. Second, some actions of kainate seem to involve the unusual interaction of an ionotropic receptor with a G protein.

Abstract

Functional kainate receptors are ubiquitous in the central nervous system. After a search for their functional significance, a considerable amount of data indicates that this class of glutamate receptors is present at both sides of the synapse. Pre- and postsynaptic kainate receptors can regulate transmission at many synapses in a specific manner, and seem to be involved in short- and long-term plastic phenomena, highlighting their significance for synaptic signalling.

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Figure 1: Pre- and postsynaptic kainate receptors in mossy fibre synapses.
Figure 2: Differential bidirectional modulation of glutamate release by presynaptic kainate receptors in the cerebellar cortex.
Figure 3: Kainate receptor-mediated modulation of GABA (γ-aminobutyric acid) release in the hippocampus.
Figure 4: Involvement of kainate receptors in long-term synaptic plasticity.

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Acknowledgements

I thank my present (O. Herreras, K. Jones, A. V. Paternain, J. L. Rozas) and former (J. C. López, A. Rodriguez-Moreno) collaborators for discussion, as well as D. Guinea for technical assistance. I thank R. Gallego (Universidad Miguel Hernández) for critical reading of the manuscript. Work in my laboratory has been supported by grants from the Spanish Ministry of Science and Technology, the Community of Madrid and the European Commission.

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  1. Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC)., Av. Doctor Arce 37, Madrid, 28002, Spain

    Juan Lerma

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DATABASES

LocusLink

GluR5

GlurR6

GluR7

GRIP

KA1

KA2

PICK

PSD95

Glossary

EC50/IC50

The concentration of an agonist or antagonist that evokes a half-maximal activation (EC50) or inhibition (IC50).

ALTERNATIVE SPLICING

During splicing, introns are excised from RNA after transcription and the cut ends are rejoined to form a continuous message. Alternative splicing gives rise to different messages from the same DNA molecule.

mRNA EDITING

Site-specific change in an RNA sequence that results in RNA anticodons, which differ from that designated by their DNA templates. In glutamate receptors, the most common change is the conversion of adenosine to inosine.

RECTIFICATION

The property whereby current through a channel does not flow with the same ease from the inside as from the outside. In inward rectification, for instance, current into the cell flows more easily than out of the cell through the same population of channels.

IN SITU HYBRIDIZATION

Method used to label cells or chromosomes having specific sequences of nucleic acids. Particularly used to identify mRNA expression in cytohistological preparations, this technique detects the formation of nucleic acid hybrid molecules between the target nucleic acid and the labelled probe containing a complementary sequence.

PARALLEL FIBRES

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 the Purkinje neurons and form the so-called en passant synapses with this cell type.

MOSSY FIBRES

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

SCHAFFER COLLATERALS

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

QUANTAL RELEASE

The release of transmitter from a single synaptic vesicle.

CHARGE TRANSFER

A measure of the magnitude of ion flow through a channel.

SPIKE THRESHOLD

The critical value of membrane potential at which a neurone or an axon will fire an action potential (spike).

STRATUM LUCIDUM

The site of termination of the mossy fibres from the dentate gyrus onto CA3 neurons of the hippocampus.

AFFERENT VOLLEY

The wave of a synaptic field potential with the shortest latency, which is proportional to the number of active presynaptic fibres. Its amplitude serves to estimate the strength of afferent input.

ELECTRICAL SHUNTING

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

ANTIDROMIC

An action potential travelling from the axon terminal towards the cell body is said to be antidromic.

HILUS

A subdivision of the hippocampus that is rich in interneurons. It is located between the CA3 region and the dentate gyrus.

SYNAPTOSOMES

Vesicles formed by a synaptic terminal generated after homogenization of nerve tissue. They preserve neurotransmitter-containing vesicles, the main machinery of release, and presynaptic receptors and channels.

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.

MINIATURE INIHIBITORY POSTSYNAPTIC CURRENTS

Synaptic currents observed in the absence of presynaptic action potentials; they are thought to correspond to the response elicited by a single vesicle of transmitter.

STRATUM ORIENS

Hippocampal layer that harbours the basal dendrites of the principal cells.

ASSOCIATIONAL/COMMISSURAL PATHWAY

The projections from CA3 neurons to other CA3 cells on the same (associational) or the opposite (commissural) side of the brain.

PHASE-LOCKED

Neurons that fire preferentially at a certain phase of an amplitude-modulated stimulus.

LONG-TERM POTENTIATION

A long-lasting increase in the efficacy of neurotransmission, which can be elicited by diverse patterns of synaptic activation.

SILENT SYNAPSE

A synapse that contains NMDA receptors but no AMPA receptors and is therefore functionally silent during low-frequency, basal synaptic transmission.

YEAST TWO-HYBRID SCREENS

System used to determine the existence of direct interactions between proteins. It involves the use of plasmids that encode two hybrid proteins; one of them is fused to the GAL4 DNA-binding domain and the other one is fused to the GAL4 activation domain. The two proteins are expressed together in yeast and, if they interact, then the resulting complex will drive the expression of a reporter gene, commonly β-galactosidase.

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).

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Lerma, J. Roles and rules of kainate receptors in synaptic transmission. Nat Rev Neurosci 4, 481–495 (2003). https://doi.org/10.1038/nrn1118

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