P2 receptors and neuronal injury

Abstract

Extracellular adenosine 5'-triphosphate (ATP) was proposed to be an activity-dependent signaling molecule that regulates glia-glia and glia-neuron communications. ATP is a neurotransmitter of its own right and, in addition, a cotransmitter of other classical transmitters such as glutamate or GABA. The effects of ATP are mediated by two receptor families belonging either to the P2X (ligand-gated cationic channels) or P2Y (G protein-coupled receptors) types. P2X receptors are responsible for rapid synaptic responses, whereas P2Y receptors mediate slow synaptic responses and other types of purinergic signaling involved in neuronal damage/regeneration. ATP may act at pre- and postsynaptic sites and therefore, it may participate in the phenomena of long-term potentiation and long-term depression of excitatory synaptic transmission. The release of ATP into the extracellular space, e.g., by exocytosis, membrane transporters, and connexin hemichannels, is a widespread physiological process. However, ATP may also leave cells through their plasma membrane damaged by inflammation, ischemia, and mechanical injury. Functional responses to the activation of multiple P2 receptors were found in neurons and glial cells under normal and pathophysiological conditions. P2 receptor-activation could either be a cause or a consequence of neuronal cell death/glial activation and may be related to detrimental and/or beneficial effects. The present review aims at demonstrating that purinergic mechanisms correlate with the etiopathology of brain insults, especially because of the massive extracellular release of ATP, adenosine, and other neurotransmitters after brain injury. We will focus in this review on the most important P2 receptor-mediated neurodegenerative and neuroprotective processes and their beneficial modulation by possible therapeutic manipulations.

Modification upon aging of the density of presynaptic modulation systems in the hippocampus

“…We have recently found that the blockade of this receptor affords a robust neuroprotection against damage of hippocampal neurons in different models of excitotoxicity (unpublished results) in agreement with the neuroprotection afforded by P2Y receptor antagonists in in vivo models of ischemia (Franke et al, 2006). We now found that the density of presynaptic hippocampal P2Y1 receptors is similar (P > 0.05) in all age groups tested (Fig.…”

“…Thus, drugs activating presynaptic modulators such as adenosine A 1 receptors (Fredholm et al, 2005) or cannabinoid CB 1 receptors (van der Stelt and Di Marzo, 2005) might afford protection against different neurodegenerative diseases. Also, antagonists of adenosine A 2A receptors (Fredholm et al, 2005), metabotropic group 5 receptors (Flor et al, 2002) or ATP P2Y1 receptors (Franke et al, 2006) also confer neu-roprotection in different animal models of brain degenerative diseases. However, the study of novel neuroprotective strategies has mostly been carried out using young adult animals, whereas most neurodegenerative diseases are prevalent in the elderly.…”

Morphological, immunocytochemical, and functional characterization of esophageal enteric neurons in primary culture

“…We therefore characterized Ca 2ϩ responses to several stimulators and inhibitors of endogenous GPCRs on the primary cultured esophageal enteric neurons. Broadly, purinergic receptors are divided into two groups: ligand-gated ion channels (P2X) and GPCRs (P2Y) (17). Several subtypes of purinergic receptors respond to ATP with increases in [Ca 2ϩ ] cyt (41).…”

A Central Role of Connexin 43 in Hypoxic Preconditioning

“…In contrast, adenosine concentrations were below detection in culture medium harvested from C6 -Cx43 Ϫ cells (data not shown). Given that C6 -Cx43 ϩ cells express both P1 and P2 purinergic receptors, ATP has the potential to activate multiple types of receptors, known to modulate the cellular injury resistance (Brismar, 1995;Abbracchio and Verderio, 2006;Franke et al, 2006;Kobayashi et al, 2006). To evaluate the relative impact of purinergic receptors on the resistance of C6 -Cx43 ϩ cells after preconditioning, we compared the effect of several P 1 or P 2 receptor antagonists.…”