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  • Review Article
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Molecular physiology of p2x receptors and atp signalling at synapses

Nature Reviews Neuroscience volume 2, pages 165–174 (2001)Cite this article

Key Points

  • There are two broad classes of ATP receptor in the nervous system: P2X and P2Y receptors. P2X receptors, a group of cation-selective ion channels, are the focus of this review. There are seven different P2X subunits, each of which has two transmembrane domains inserted in the plasma membrane such that both the amino and the carboxyl termini are located intracellularly.

  • The ATP-binding site of P2X receptors seems to be located near the transmembrane domains and is thought to involve several lysine residues. The second transmembrane domain of P2X subunits forms the channel pore, which is permeable to different cations including calcium. Although their exact subunit stochiometry is controversial, most of the evidence supports the idea that P2X receptors assemble as trimers.

  • P2X receptors are ubiquitously expressed in the nervous system. Indeed, they are present both pre- and postsynaptically. Activation of presynaptic P2X receptors can modulate release of several neurotransmitters at a variety of synapses. Postsynaptically, ATP can elicit excitatory synaptic currents in some cells, but they seem to contribute to a small part of the total excitatory drive.

  • P2X receptors have been implicated in processing pain information. ATP released from damaged tissue can act directly on P2X receptors present in the primary sensory afferent. In turn, the terminals of sensory neurons release ATP onto dorsal horn cells. In addition, presynaptic receptors on the terminals of the sensory neuron facilitate the release of glutamate onto dorsal horn cells, and presynaptic P2X receptors on inhibitory nerve terminals also facilitate the release of GABA and glycine. The balance between inhibitory and excitatory effects contributes to the spinal processing of painful information.

Abstract

ATP is found in every cell, where it is a major source of energy. But in the nervous system, ATP also has additional actions, which include its role in fast synaptic transmission and modulation. Here I discuss the 'fast' actions of ATP at synapses, the properties of the receptors that are activated by ATP and the physiology of ATP signalling, with emphasis on its role in pain processing.

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Figure 1: Fast and slow responses to ATP.
Figure 2: A representation of P2X subunit structure and function.
Figure 3: Role of fast ATP signalling in detecting and processing of pain.

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Acknowledgements

While at Caltech, B.S.K. was supported by a Wellcome Trust (UK) International Prize Travelling Research Fellowship and Roche Bioscience (Palo Alto). Many thanks to Cesar Labarca for comments on the paper and to Henry A. Lester for encouragement.

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Authors and Affiliations

  1. MRC Laboratory of Molecular Biology, Cambridge, CB2 2QH, UK

    Baljit S. Khakh

  2. Division of Biology, California Institute of Technology, Pasadena, 91125, California, USA

    Baljit S. Khakh

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DATABASE LINKS

P2X6

P2X7

P2X2

P2X1

P2X4

P2X3

P2X5

FURTHER INFORMATION

The ligand-gated ion channels database

The ion channel network

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Glossary

AUERBACHS PLEXUS

A collection of nerves and ganglia located between the circular and longitudinal muscles in the small intestine. It is also known as the myenteric plexus.

CHROMAFFIN CELLS

Cells of the adrenal gland that store and secrete catecholamines. They are termed 'chromaffin' because of the ability of chromium salts to stain them.

ECTOATPASES

A general term for the extracellular enzymes that hydrolyse ATP.

LEADER SEQUENCE

A stretch of hydrophobic residues at the amino-terminal end of some proteins, which directs them to the plasma membrane or to the membrane of specific cellular organelles.

P REGION

A conserved structural motif found in all K+-selective ion channels, which constitutes part of the channel pore.

POTENCY

A measure of the change in response as a function of ligand concentration. Agonist potency is quantified as the concentration of ligand that produces half the maximal effect (EC50). The classic pharmacological definition of potency thus includes components of affinity and efficacy. In such schemes, efficacy is simply the ability of a drug to evoke a response once bound. Potency is related to affinity, but potency and affinity are different measures of drug action.

ALANINE SCANNING MUTAGENESIS

This method is used to obtain a preliminary profile of the functionally important regions of a protein. It is based on the systematic replacement of amino acids into alanine and the subsequent analysis of the effect of the mutation on the function of the protein.

SCHIFF BASE

A reversible bond formed by the condensation of carbonyl and amino groups.

SUBSTITUTED CYSTEINE ACCESSIBILITY MUTAGENESIS

A method used to identify the residues that are likely to line the pore of a channel. It is based on the systematic replacement of native amino acids by cysteines to then test the ability of hydrophilic molecules to react with the added cysteines. If a cysteine is accessible to the hydrophilic reagent, then channel permeability will be affected.

SYNAPTOSOME

The presynaptic terminal isolated after subcellular fractionation. This structure retains the anatomical integrity of the terminal and can take up, store and release neurotransmitters.

MINIATURE EPSCs

Excitatory synaptic currents observed in the absence of presynaptic action potentials, thought to correspond to the response elicited by a single vesicle of transmitter.

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Khakh, B. Molecular physiology of p2x receptors and atp signalling at synapses . Nat Rev Neurosci 2, 165–174 (2001). https://doi.org/10.1038/35058521

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