Molecular Biology of P2X Purinoceptors

Abstract

A major class of ATP receptor, the P2X purinoceptor, operates an ion-channel intrinsic to the quaternary structure of the receptor proteia ATP-gated ionchannels are permeable to monovalent (Na+ and K+) and divalent cations (Ca2+), but charge selection precludes the passage of anions. The channel pore is approximately 9A in diameter. Estimates of Pca/PNa ratios vary widely (0.3 to 10) amongst known examples of recombinant and native P2X receptors, whereas the pore shows no such selectivity for monovalent cations (PK/PNa ~1). Thus, P2X ion-channels permit physiologically-significant levels of Ca2+-influx into cells at voltages near the resting membrane potential. Since 1994, seven types of P2X receptor subunits (P2X1-7) have been cloned and the pharmacology of homomeric P2X1-7 receptors studied. However, little is known with certainty about the ways P2X subunits combine to form an ion-channel — in terms of receptor stoichiometry, the lining of the ion pore, means by which the ionchannel opens and closes, allosteric modulatory sites, the ligand docking site and reasons for selectivity of nucleotidic analogues. The situation has been compounded by the discovery of splice variants of P2X subunits, which alter the operational profile of recombinant P2X receptors. However, advances have been made in understanding these basic properties by carefully studying the operational features of cloned P2X receptors expressed as either homomeric or heteromeric assemblies of P2X subunits in mammalian and non-mammalian host cells. The predicted amino acid sequences of the seven known P2X subunits varies significantly, showing between 32% and 52% sequence identity between subunit proteins. However, the topology of P2X1-7 subunits is unerringly alike and key domains have been identified as having a bearing on operational features of the P2X purinoceptor. The possibility exists that P2X1-7 subunits and their splice variants can produce a large number of permutations of heteromeric P2X purinoceptors. Nonetheless, emerging evidence indicates that structural diversity between P2X subunits actually limits their potential for union and, if polymerisation does occur, a single P2X subunit tends to dominate by conferring key phenotypic properties to native P2X purinoceptors.