Abstract
P2X receptors are ATP-gated non-selective cation channels involved in many different physiological processes, such as synaptic transmission, inflammation, and neuropathic pain. They form homo- or heterotrimeric complexes and contain three ATP-binding sites in their extracellular domain. The recent determination of X-ray structures of a P2X receptor solved in two states, a resting closed state and an ATP-bound, open-channel state, has provided unprecedented information not only regarding the three-dimensional shape of the receptor, but also on putative conformational changes that couple ATP binding to channel opening. These data provide a structural template for interpreting the huge amount of functional, mutagenesis, and biochemical data collected during more than fifteen years. In particular, the interfacial location of the ATP binding site and ATP orientation have been successfully confirmed by these structural studies. It appears that ATP binds to inter-subunit cavities shaped like open jaws, whose tightening induces the opening of the ion channel. These structural data thus represent a firm basis for understanding the activation mechanism of P2X receptors.
Highlights
ATP-gated P2X receptors are involved in a variety of physiological processes such as fast synaptic transmission, contraction of smooth muscle, regulation of neurotransmitter release, inflammation, and pain sensation (Surprenant and North, 2009; Burnstock, 2012; Khakh and North, 2012)
Following ATP binding in the ectodomain which is about 280 amino acids long, a fast and large conformational change occurs throughout the receptor that results in pore opening (Evans, 2009; Jiang et al, 2013)
ALLOSTERIC REPORTER MUTATIONS The first evidence distinguishing ATP binding from gating in P2X receptors was provided by Cao et al (2007), where the authors combined single-channel recordings and the use of a mutated receptor considered as an “allosteric reporter.”
Summary
ATP-gated P2X receptors are involved in a variety of physiological processes such as fast synaptic transmission, contraction of smooth muscle, regulation of neurotransmitter release, inflammation, and pain sensation (Surprenant and North, 2009; Burnstock, 2012; Khakh and North, 2012). Following ATP binding in the ectodomain which is about 280 amino acids long, a fast and large conformational change occurs throughout the receptor that results in pore opening (Evans, 2009; Jiang et al, 2013) Many different strategies such as site-directed mutagenesis, electrophysiological recordings, fluorescence-based approaches, and X-ray crystallography have contributed to the understanding of the mechanism by which ATP-binding is coupled to gating. The role of the conserved amino acids of the extracellular loop has been systematically investigated using site-directed mutagenesis This method has led to the identification of short domains and specific residues such as lysine, arginine, and phenylalanine putatively involved in ATP recognition. These investigations have yielded substantial information for the modeling of the interaction between ATP and its specific binding site
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