Subtype-Specific Control of P2X Receptor Signaling by ATP and Magnesium

Abstract

The identity and forms of activating ligands for ion channels are fundamental to their physiological roles in rapid electrical signaling. P2X receptor channels are ATP-activated cation channels that serve important roles in sensory signaling and inflammation, yet the active forms of the nucleotide are unknown. In physiological solutions, ATP is ionized and primarily found in complex with Mg2+. In this study we investigated the active forms of ATP and find that the action of MgATP2- and ATP4- differ between subtypes of P2X receptors. The slowly desensitizing P2X2 receptor can be activated by free ATP, but MgATP2- promotes opening with very low efficacy. In contrast, both free ATP and MgATP2- robustly open the rapidly desensitizing P2X3 subtype. A further distinction between these two subtypes is the ability of Mg2+ to regulate P2X3 through a distinct allosteric mechanism. Importantly, heteromeric P2X2/3 channels present in sensory neurons exhibit a hybrid phenotype, characterized by robust activation by MgATP2- and weak regulation by Mg2+. These results reveal the existence of two classes of homomeric P2X receptors with differential sensitivity to MgATP2- and regulation by Mg2+, and demonstrate that both restraining mechanisms can be disengaged in heteromeric P2X2/3 receptor channels. We are currently investigating if our findings with P2X2/3 receptor channels can be generalized to other subtypes of homomeric and heteromeric P2X receptors.