Regulation of P2X7 receptor expression and function in the brain

Because of its prominent role in driving inflammatory processes, the ATP-gated purinergic P2X7 receptor has attracted much attention over the past decade as a potential therapeutic target for numerous human conditions, particularly diseases of the central nervous system, including neurodegenerative diseases (e.g. Alzheimer's and Huntington's disease), psychiatric disorders (e.g. schizophrenia and depression) and the neurological disease, epilepsy. Evidence stems from studies using experimental models and patient tissue showing changes in P2X7 expression and function under pathological conditions and beneficial effects provided by P2X7 antagonism. Apart from promoting neuroinflammation, P2X7, however, also impacts on other pathological processes in the brain, including cell death, hyperexcitability, changes in neurotransmitter release and neurogenesis. Reports also suggest a role for P2X7 in the maintenance of blood-brain-barrier integrity. It therefore comes as no surprise that the regulation of P2X7 expression and function is complex, providing tight control on P2X7 activation. Much progress has been made in understanding how P2X7 is regulated during physiological and pathological conditions and what the consequences are of pathological P2X7 expression and function. Regulatory mechanisms altering P2X7 expression include transcriptional and post-translational regulation including nucleotide polymorphisms, promoter regulation via DNA methylation, transcription factors (e.g. Sp1 and HIF-1 alpha), the generation of different splice variants and receptor phosphorylation, glycosylation and palmitoylation. Finally, more recently, reports have also shown P2X7-targeting by microRNAs, blocking P2X7 translation into functional proteins. The present review provides a broad overview of what is known to-date about the complex regulation of P2X7 expression with a particular emphasis on the brain and how each of these regulatory mechanisms impacts on receptor function and pathology.