Therapeutic potential of extracellular ATP and P2 receptors in nervous system diseases

Abstract

Extracellular adenosine 5'-triphosphate (ATP) is a key signaling molecule present in the central nervous system (CNS), and now is receiving greater attention due to its role as a messenger in the CNS during different physiological and pathological events. ATP is released into the extracellular space through vesicular exocytosis or from damaged and dying cells. Once in the extracellular environment, ATP binds to the specific receptors termed P2, which mediate ATP effects and are present broadly in both neurons and glial cells. There are P2X, the ligand-gated ionotropic receptors, possessing low affinity for ATP and responsible for fast excitatory neurotransmission, and P2Y, the metabotropic G-protein-coupled receptors, possessing high affinity for ATP. Since massive extracellular release of ATP often occurs after stress, brain ischemia and trauma, the extracellular ATP is considered relating to or involving in the pathological processes of many nervous system diseases. Conversely, the trophic functions have also been extensively described for the extracellular ATP. Therefore, extracellular ATP plays a very complex role in the CNS and its binding to P2 receptors can be related to toxic and/or beneficial effects. In this review, we described the extracellular ATP acting via P2 receptors as a potent therapeutic target for treatment of nervous system diseases.

Insertion of proteolipid protein into oligodendrocyte mitochondria regulates extracellular pH and adenosine triphosphate

“…Only slight increases of ATP in ECF or in media are sufficient to initiate microglial activation. Microglia move to areas of increased extracellular ATP/ADP that cause mitogenesis and cytokine release (Agteresch et al, ; Delarasse et al, ; Honda et al, ; Melani et al, ; Neary et al, ; Samuels et al, ; Shigemoto‐Mogami et al, ; Tu and Wang, ). Similarly, extracellular acidosis in many different types of tissues, including brain, initiates a host of molecular reactions that may culminate in tumor progression, pain, and irreversible brain damage (e.g., Chesler, ; Dubé et al, ; Wang et al, ).…”

“…We further show that mutations of these PLP cysteines prevents insertion of PLP into mitochondria, and prevents the acidification of tissue culture media and decreases adenosine triphosphate (ATP) levels in the media. These findings are highly relevant to neuronal degeneration because increased ATP levels in media and in ECF activate cytokines via receptors on microglia and astrocytes that, in turn, lead to neuronal degeneration (Agteresch et al, ; Delarasse et al, ; Honda et al, ; Melani et al, ; Neary et al, ; Samuels et al, ; Shigemoto‐Mogami et al, ; Tu and Wang, ).…”

Astrocytic P2Y1 receptor is involved in the regulation of cytokine/chemokine transcription and cerebral damage in a rat model of cerebral ischemia

“…Several P2 receptors have been implicated in cerebral ischemic brain damage. For instance, the P2X1, P2X2, P2X4, P2X7, and P2Y 1 receptors (P2Y 1 Rs) are upregulated in neurons or glial cells in various brain regions after ischemia (Tu and Wang, 2009), and a significant reduction in infarct volume has been observed following treatment with pyridoxal-phosphate-6-azophenyl-2 0 ,4 0 -disulfonic acid, a P2 receptor antagonist (Lammer et al, 2006). Thus, P2 receptors are thought to have a key role in the pathophysiology of cerebral ischemia.…”

P2Y6 receptor and immunoinflammation

“…Nucleotide receptors are normally divided into two categories: P1 receptors that bind to adenosine in a concentration-dependent way and have diverse biological functions through G-protein linked second-messenger systems, and P2 purinoceptors that are further divided into two families: ionotropic receptors (P2X) family and metabotropic receptors (P2Y) family. P2X receptors (7 types: P2X1-P2X7) contain intrinsic pores that are opened following ATP binding [1] . P2Y receptors (8 types: P2Y1, 2, 4, 6, 11, 12, 13 and 14) are activated by nucleotides and linked to intracellular second-messenger systems through heteromeric G-proteins.…”