Role of Purinergic Receptors in CNS Function and Neuroprotection

Abstract

The purinergic receptor family contains some of the most abundant receptors in living organisms. A growing body of evidence indicates that extracellular nucleotides play important roles in the regulation of neuronal and glial functions in the nervous system through purinergic receptors. Nucleotides are released from or leaked through nonexcitable cells and neurons during normal physiological and pathophysiological conditions. Ionotropic P2X and metabotropic P2Y purinergic receptors are expressed in the central nervous system (CNS), participate in the synaptic processes, and mediate intercellular communications between neuron and gila and between glia and other glia. Glial cells in the CNS are classified into astrocytes, oligodendrocytes, and microglia. Astrocytes express many types of purinergic receptors, which are integral to their activation. Astrocytes release adenosine triphosphate (ATP) as a “gliotransmitter” that allows communication with neurons, the vascular walls of capillaries, oligodendrocytes, and microglia. Oligodendrocytes are myelin-forming cells that construct insulating layers of myelin sheets around axons, and using purinergic receptor signaling for their development and for myelination. Microglia also express many types of purinergic receptors and are known to function as immunocompetent cells in the CNS. ATP and other nucleotides work as “warning molecules” especially by activating microglia in pathophysiological conditions. Studies on purinergic signaling could facilitate the development of novel therapeutic strategies for disorder of the CNS.

Introduction

In 1972, Burnstock first proposed a role for nucleotides as neurotransmitters (Burnstock, 1972). In 1993, the first receptors for nucleotides, called P2 purinoceptors, were cloned (Lustig et al., 1993, Webb et al., 1993). During the past two decades, evidences have accumulated for the participation of extracellular nucleotides and nucleosides as neurotransmitters in neuronal signaling (Burnstock, 2007a). Numerous subtypes of these receptors were cloned, and subsequently, the field of purinergic nervous system has been widely accepted by scientists. Purine-sensitive receptors were first classified as P1 G-coupled receptors, which are activated by adenosine and purinergic receptors, and respond to adenosine triphosphate (ATP) stimulation (Burnstock & Kennedy, 1985). Based on receptor cloning and receptor-induced signal transduction, purinergic receptors were subdivided into ATP-gated ionotropic receptors (P2X) and G protein-coupled metabotropic receptors (P2Y; Abbracchio et al., 2006, Khakh et al., 2001). Accumulating evidences indicate that nucleotides are released from and leaked through nonexcitable cells and neurons and are involved in cell-to-cell communication during normal physiological and pathophysiological conditions (Abbracchio et al., 2009, Fields and Burnstock, 2006). We now have vast amount of information indicating the ubiquitous presence of purinergic signaling throughout the body.

ATP and uridine triphosphate (UTP) and their metabolites are the main purinergic agonists that activate P2X or P2Y receptors. It is known that activation of purinergic receptors often results in increased intracellular free calcium concentrations. Changes in calcium are involved in the regulation of many physiological processes in the central nervous system (CNS; Burnstock, 2007a). In the extracellular space, ecto-enzymes rapidly degrade these nucleotides to ADP or UDP, subsequently activating distinct P2Y receptors. Alternatively, these nucleotides can be finally degraded to adenosine, which activates P1 receptors (Burnstock, 2007b).

Glial cells make up over 70% of the total cell population in the CNS. Astrocytes express many types of P2X/Y receptors and release ATP spontaneously or in response to various stimuli (Verkhratsky et al., 2009). Further, astrocytes communicate with neurons at synapses, with oligodendrocytes, microglial cells, and the vascular walls of capillaries (Abbracchio et al., 2009, Iadecola and Nedergaard, 2007, Inoue et al., 2007). Microglia are known as the resident macrophages of the CNS and express many types of purinergic receptors (Farber and Kettenmann, 2006, Inoue, 2008). Oligodendrocytes are myelin-forming cells that construct insulating layers of myelin sheets around axons in the CNS and utilize both P1 and purinergic receptors for their development (Fields & Stevens-Graham, 2002). Although it was traditionally believed that glial cells are the only source of physical and metabolic supports in the nervous system for neurons, a growing body of evidence has dramatically changed this classical view. An emerging conceptualization of glial cells indicates that neuron–glia interactions are a key component of the CNS functions, and purinergic signaling is one of its mediators (Abbracchio et al., 2009). In addition to crucial roles in normal physiological conditions, purinergic signaling plays an important role in pathophysiological conditions of the CNS (Burnstock, 2008) including physical trauma, cerebral ischemia, neurodegenerative diseases, neuroinflammatory disorders, neuropsychiatric disorders, and neuropathic pain (Table I). In this chapter, an overview of studies on the role of the purinergic receptors in physiological and pathophysiological processes of the cell types forming CNS will be presented. Large amounts of hints for developing new drugs for neuroprotection may be buried in these fundamental studies.