Purinergic trophic signalling in glial cells: functional effects and modulation of cell proliferation, differentiation, and death

In the last decades, the discovery that glial cells do not only fill in the empty space among neurons or furnish them with trophic support but are rather essential participants to the various activities of the central and peripheral nervous system has fostered the search for the signalling pathways controlling their functions. Since the early 1990s, purines were foreseen as some of the most promising candidate molecules. Originally just a hypothesis, this has become a certainty as experimental evidence accumulated over years, as demonstrated by the exponentially growing number of articles related to the role of extracellular nucleotides and nucleosides in controlling glial cell functions. Indeed, as new functions for already known glial cells (for example, the ability of parenchymal astrocytes to behave as stem cells) or new subtypes of glial cells (for example, NG2(+) cells, also called polydendrocytes) are discovered also, new actions and new targets for the purinergic system are identified. Thus, glial purinergic receptors have emerged as new possible pharmacological targets for various acute and chronic pathologies, such as stroke, traumatic brain and spinal cord injury, demyelinating diseases, trigeminal pain and migraine, and retinopathies. In this article, we will summarize the most important and promising actions mediated by extracellular purines and pyrimidines in controlling the functions, survival, and differentiation of the various "classical" types of glial cells (i.e., astrocytes, oligodendrocytes, microglial cells, Müller cells, satellite glial cells, and enteric glial cells) but also of some rather new members of the family (e.g., polydendrocytes) and of other cells somehow related to glial cells (e.g., pericytes and spinal cord ependymal cells).