P2X Receptors and Their Roles in Astroglia in the Central and Peripheral Nervous System

Abstract

Astrocytes are a class of neural cells that control homeostasis at all levels of the central and peripheral nervous system. There is a bidirectional neuron–glia interaction via a number of extracellular signaling molecules, glutamate and ATP being the most widespread. ATP activates ionotropic P2X and metabotropic P2Y receptors, which operate in both neurons and astrocytes. Morphological, biochemical, and functional evidence indicates the expression of astroglial P2X_1/5 heteromeric and P2X₇ homomeric receptors, which mediate physiological and pathophysiological responses. Activation of P2X_1/5 receptors triggers rapid increase of intracellular Na⁺ that initiates immediate cellular reactions, such as the depression of the glutamate transporter to keep high glutamate concentrations in the synaptic cleft, the activation of the local lactate shuttle to supply energy substrate to pre- and postsynaptic neuronal structures, and the reversal of the Na⁺/Ca²⁺ exchange resulting in additional Ca²⁺ entry. The consequences of P2X₇ receptor activation are mostly but not exclusively mediated by the entry of Ca²⁺ and result in reorganization of the cytoskeleton, inflammation, apoptosis/necrosis, and proliferation, usually at a prolonged time scale. Thus, astroglia detect by P2X_1/5 and P2X₇ receptors both physiological concentrations of ATP secreted from presynaptic nerve terminals and also much higher concentrations of ATP attained under pathological conditions.