ATP-gated P2X channels

Abstract

What are they? P2X channels are a family of cell-membrane cation channels which open within milliseconds of binding ATP. They are distinct from the other family of ATP receptors, the G-protein-coupled P2Y receptors, and also from other transmitter-gated ion channels. P2X channels are the third major family of mammalian transmitter-gated ion channels (Figure 1Figure 1); they are similar in topology to amiloride-sensitive sodium channels.Figure 1Presently understood membrane topology for mammalian neurotransmitter-gated ion channels. The pink segments indicate pore lining parts of the proteins.View Large Image | View Hi-Res Image | Download PowerPoint SlideWhat is the importance of extracellular ATP? ATP is abundant inside cells, where it provides the energy for many biological reactions. Outside the cell, however, ATP is at a much lower level and it can bind to receptors on different cell types to cause a range of effects. ATP can act as a neurotransmitter or activate neurons and immune cells when it is released from damaged cells. Although initially disputed, there now appears to be strong evidence that ATP is an extracellular signaling molecule in a whole host of cell types. Geoffrey Burnstock first put forward this hypothesis over thirty years ago.How many different P2X receptors exist? So far, seven different mammalian P2X subunits have been discovered (P2X1–P2X7), ranging from 379 (P2X6) to 595 (P2X7) amino acids in length. Apart from P2X7, they can all associate with other subunits to form heteromeric channels. Also, apart from P2X6, they are functional as homomeric receptors. A functional receptor is thought to be trimeric, so the possibility for heteromeric assemblies is quite large.What is the structure of each subunit? We don't have an atomic-scale view, but each subunit has two membrane-spanning regions, TM1 and TM2, separated by a large extracellular domain. TM1 and TM2 probably line the pore. The extracellular loop has ten conserved cysteine residues, a number of glycosylation sites and the ATP-binding site near TM1. The amino and carboxyl termini are cytoplasmic. The amino terminus is quite short and has a PKC phosphorylation site important for desensitisation. The carboxyl terminus varies widely in length, P2X7 having the longest tail. In some P2X channels it too plays a role in desensitisation, pore dilation and docking of cytosolic protein partners.What happens when ATP binds to the P2X receptor? It causes a conformational change in the shape of the receptor. The pore opens to allow small cations such as Na+ and K+, and variable amounts of Ca2+, to pass through. The membrane becomes depolarised as the inwardly rectifying current flows. Depending on the location, concentration of ATP and type of P2X receptor, the depolarisation may trigger initiation of an action potential in a neuron, and/or other intracellular events, often as a result of the increased intracellular Ca2+ concentration. P2X1 and P2X3 receptors desensitise in milliseconds; others take about 100–1000 times longer, if at all, to stop responding to ATP. Some P2X channels have two permeability states. The pore can dilate with prolonged application of ATP to allow larger cations to flow. The pore thus goes from closed to open to enlarged.Where are the receptors located and what functions do they have? They are found in cells all over the body. P2X1 receptors are mainly found on smooth muscle, where they cause contraction, and P2X1 knockout mice have impaired fertility. P2X3 receptors are noted for their role in nociception. The main targets for ATP released at CNS synapses may be P2X2 and P2X4 channels, but decisive evidence is lacking. P2X5 has been found in many locations including the brain, heart, thymus and in particular skeletal muscle where it has been shown to regulate differentiation and control cell fate. P2X7 receptors are on most cells of the immune system. Activation can lead to a wide range of downstream events such as cell permeabilisation, apoptosis, and release of interleukins.Where can I find out more?