Purinergic Signaling in the Central Nervous System in Health and Disease

The existence of purinergic signaling—the idea that almost all cells of the animal/human organism are able to communicate with each other via extracellular purines—was proposed by Geoffrey Burnstock (1929–2020) in 1972 [1–3]. The purinergic system includes the following constituents: (1) the four main purines: adenosine triphosphate (ATP) and its metabolites, adenosine diphosphate (ADP), adenosine monophosphate (AMP), and adenosine (ADO); (2) three key enzymes, the ectonucleoside triphosphate diphosphohydrolases (E-NTPDases: NTPDase 1/CD39), ectonucleotide pyrophosphatase/phosphodiesterases (E-NPP), and ecto-5′-nucleotidase (E-5′-nucleotidase/CD73), which decompose ATP into ADP, AMP, and ADO; and (3) nineteen purinergic receptors: four subtypes of G protein-coupled P1 receptors (A1, A2A, A2B, and A3), seven subtypes of ligand-gated cationic channels (P2X1-7), and eight subtypes of metabotropic G protein-coupled receptors (P2Y1, 2, 4, 6, and 11–14) [4, 5]. ATP was described originally as a co-transmitter with classic transmitters such as noradrenaline and acetylcholine in the peripheral vegetative nervous system [6]. Later, ATP was identified as a transmitter and signaling molecule in its own right and a molecule participating in intercellular signal transduction [7]. In the central nervous system (CNS), purinergic signaling plays an important role in maintaining the functions of neurons, astrocytes, and microglia, and regulating their homeostasis, with consequences for synaptic transmission and higher-order cognitive processes [8, 9]. For instance, ADO and the activation of A1 receptors contribute to sleep homeostasis [10, 11], while in contrast, the inhibition of A2A receptors leads to sleep disorder [12]. Furthermore, neuronal P2X3 receptors (mainly expressed in neurons) and glial P2 receptors (P2X4, P2X7, P2Y1, and P2Y12 in microglia; P2X7 and P2Y1 receptors in astrocytes; P2X7, P2Y1, and P2Y12 receptors in oligodendrocytes) have been demonstrated to participate in neuroinflammation or neuron-microglia, neuron-astrocyte, and neuron-oligodendrocyte interactions, as well as microglia-neuron, astrocyte-neuron, and oligodendrocyte-neuron interactions, and finally in astrocyte-microglia and microglia-oligodendrocyte interactions [13–17]. In recent decades, the pathological potential of purinergic signaling that contributes to and aggravates various types of neurodegenerative illnesses (Alzheimer’s, Parkinson’s and Huntington’s disease as well as multiple sclerosis and amyotrophic lateral sclerosis) has been increasingly acknowledged [8, 9, 18, 19]. Nucleotides are also fundamental for the pathological evolution of trauma, ischemia, stroke, and epilepsy, in which they mediate both acute and secondary neurodegeneration [20, 21]. In the clinic, single nucleotide polymorphisms of A2A and P2X7 receptors may serve as potential indicators for the early risk assessment of CNS disorders [22–24]. Drugs (such as istradefylline, dipyridamole, suramin, clopidogrel, prasugrel, cangrelor, and ticagrelor) targeted to purinergic signaling and approved by the US Food and Drug Administration have beneficial effects on a variety of neurological diseases [25–27] and further drugs still in development may open new avenues in fighting a multitude of CNS diseases [28, 29].

Three original articles, 4 reviews, and 1 insight paper are included in this special topic. Li et al. [30] demonstrated that an increased concentration of extracellular ATP and activated astroglial P2X7 receptors are responsible for chronic sleep deprivation-induced depressive-like behavior in mice. Engel et al. [31] used a transgenic mouse model overexpressing P2X7 fused to the fluorescent protein EGFP to visualize P2X7 receptor expression. They found that increased P2X7-EGFP expression was localized in microglia and oligodendrocytes of the hippocampus, cortex, striatum, thalamus, and cerebellum after intra-amygdala kainic acid injection that caused epilepsy or even status epilepticus. Xu et al. [32] showed that neonatal maternal deprivation followed by adult multiple stress led to P2X3 receptor activation, which is most likely mediated by upregulation of β2 adrenergic signaling in primary sensory neurons, thus contributing to visceral hypersensitivity. Milenkovic et al. [33] concentrated on purinergic modulation of neuronal activity in the developing auditory system and provided new models of the contribution of purinergic signaling to early development of the afferent auditory pathway. The review by Boue-Grabot et al. [34] focused on the contribution of neuronal and glial P2X4 receptors to pathological CNS states and proposed that these receptors are a potential therapeutic target in CNS diseases. Ulrich et al. [35] discussed the role of purinergic receptors in the molecular mechanisms shared by Huntington’s and Parkinson’s diseases and proposed that A2A and P2X7 receptor antagonists might be promising therapeutic agents for their treatment. Frenguelli et al. [36] summarized the developments in translational research on purines from diagnostic biomarkers to therapeutic agents in brain injury. In the insight of Illes et al. [37], it is pointed out that the decreased astrocytic release of ATP and activation of P2X7 receptors in the medial prefrontal cortex and hippocampus may play important roles in the development of major depressive disease.

We strongly believe that the comprehensive reviews listed above allow profound insights into the purinergic modulation of CNS functions in health and disease, and thereby represent a significant increase of our knowledge in the purine field.