Membrane compartments and purinergic signalling: P2X receptors in neurodegenerative and neuroinflammatory events

Abstract

ATP is a potent signalling molecule abundantly present in the nervous system, where it exerts physiological actions ranging from short‐term responses such as neurotransmission, neuromodulation and glial communication, to long‐term effects such as trophic actions. The fast signalling targets of extracellular ATP are represented by the ionotropic P2X receptors, which are broadly and abundantly expressed in neurons and glia in the whole central and peripheral nervous systems. Because massive extracellular release of ATP often occurs by lytic and non‐lytic mechanisms, especially after stressful events and pathological conditions, purinergic signalling is correlated to and involved in the aetiopathology and/or progression of many neurodegenerative diseases. In this minireview, we highlight the contribution of the subclass of ionotropic P2X receptors to several diseases of the human nervous system, such as neurodegenerative disorders and immune‐mediated neuroinflammatory dysfunctions including ischaemia, Parkinson’s, Alzheimer’s and Huntington’s diseases, amyotrophic lateral sclerosis and multiple sclerosis. The role of P2X receptors as novel and effective targets for the genetic/pharmacological manipulation of purinergic mechanisms in several neuropathological conditions is now well established. Nevertheless, any successful therapeutic intervention against these diseases cannot be restricted to P2X receptors, but should take into consideration the whole and multipart ATP signalling machinery.

The Proinflammatory Action of Microglial P2 Receptors Is Enhanced in SOD1 Models for Amyotrophic Lateral Sclerosis

“…Because the physiological relevance of extracellular nucleotides to ALS depends on the accessibility of these molecules in the environment surrounding microglia, and the net outcome of inflammation relates also to the duration of the initial damage, it is important to ask where the local concentration of nucleotides triggering and sustaining the purinergic machinery might indeed come from. ATP is secreted by a variety of cell types in the CNS, including neurons, activated astrocytes, and microglia (52). Functionally autocrine mechanisms of ATP secretion and binding for instance to the P2X 7 receptors have been shown to mediate LPS-induced IL-1␤ secretion from microglia (53).…”

Spatiotemporal characteristics of calcium dynamics in astrocytes

“…Fig. 1͑a͔͒ that can be summarized as follows: 67 ͑1͒ the ligand and receptor kinetics at the plasma membrane ͑the input module͒, ͑2͒ a G q -type G-protein-activated module in which activated phospholipase C ͑PLC͒ leads to the production of IP 3 and diacylglycerol ͑DAG͒ from phosphatidylinositol-biphosphate ͑PIP 2 ͒ ͑the amplifying module͒, ͑3͒ an IP 3 / IP 3 -receptor system that controls the Ca 2+ release from the ER by calcium-induced calcium release ͑CICR͒ ͑the output module͒, and ͑4͒ a feedback module involving DAG-Ca 2+ activation of protein kincase C ͑PKC͒, which leads to downregulation of receptors and PLC ͑the feedback module͒. The input module receives stimulatory ligand and inhibitory PKC signals as inputs and produces G ␣ and G ␤␥ as outputs, the former of which serves as an input to the amplifying module.…”

“…The input module receives stimulatory ligand and inhibitory PKC signals as inputs and produces G ␣ and G ␤␥ as outputs, the former of which serves as an input to the amplifying module. The amplifying module produces its outputs, IP 3 and DAG, from the hydrolysis of PIP 2 by G ␣ -activated PLC. While soluble IP 3 diffuses into the cytoplasm and functions as an input to the output module, hydrophobic DAG stays at the inner leaflet of the plasma membrane.…”

“…While soluble IP 3 diffuses into the cytoplasm and functions as an input to the output module, hydrophobic DAG stays at the inner leaflet of the plasma membrane. The output module comprises the Ca 2+ handling mechanisms such as IP 3 -stimulated release from the ER and Sarco/Endoplasmic Reticulum calcium ATPase ͑SERCA͒ uptake and outputs Ca i 2+ . Finally, the feedback module receives Ca i 2+ and DAG as inputs and produces the activated state of PKC, which downregulates the activity of input and amplifying modules.…”

High dose of extracellular ATP switched autophagy to apoptosis in anchorage-dependent and anchorage-independent hepatoma cells

“…In response to tissue damage and cellular stress, intracellular ATP is actively released into the extracellular environment and acts as an important signaling molecule [1]. Extracellular ATP (eATP) exerts many functions in physiological and pathological conditions, and its effect on cells is mediated by ionotropic (P2X) and metabotropic (P2Y) receptors [2][3][4]. Extracellular ATP could be hydrolyzed by ectonucleotidases; thus, its concentration is maintained at very low level in physiological conditions [5].…”