Subtype Specific Activation of P2X Receptors by Free and Magnesium-Bound ATP

Abstract

P2X receptors are cation-selective channels that were suggested to play roles in many important physiological processes, including muscle contraction, pain sensation, and inflammation. Extracellular ATP released from various sources, such as synaptic vesicles and damaged cells, is the ligand for activating P2X receptors. In neutral solution, ATP is ionized and exists mostly as free ATP (ATP4-), a high affinity chelator for divalent and trivalent cations. As there are millimolar divalent cations present in the extracellular milieu, it is likely that most extracellular ATP released from synaptic vesicles is chelated by divalent. We found that some subtypes of P2X receptors can be activated by both free and divalent-bound ATP, while others can only be efficiently activated by free ATP. This subtype specific activation by different forms of ATP parallels the pharmacological sensitivity to other agonists and antagonists, pointing to the existence of two distinct classes of ligand binding pockets. We are currently examining which forms of ATP activate heteromeric P2X receptor channels formed by subunits with different sensitivity to divalent-bound ATP.