Gain and Loss of Function of P2X₇ Receptors: Mechanisms, Pharmacology and Relevance to Diabetic Neuropathic Pain

Abstract

BackgroundGenetic causes of exaggerated or reduced pain sensitivity in humans are well known. Recently, single nucleotide polymorphisms (SNPs) in the gene P2RX7, coding for the ATP-gated ion channel P2X7, have been described that cause gain-of-function (GOF) and loss-of-function (LOF), respectively of this channel. Importantly, P2RX7 SNPs have been associated with more or less severe pain scores in patient suffering of post-mastectomy pain and osteoarthritis.ResultsThe functional consequences of some P2RX7 SNPs (rs208294 (His155Tyr), rs1718119 (Ala348Thr) and rs3751143 (Glu496Ala)) were studied in recombinant cells in vitro. Our findings suggest a correlation between GOF and LOF of P2X7 and actual channel protein expression. Both channel and pore function for these mutant P2X7 receptors changed in parallel to protein levels. On the other hand, the mutant receptors did not differ in their sensitivity to known P2X7 agonists and antagonists. We further demonstrated that in patients with diabetic peripheral neuropathic pain (DPNP), the presence of the GOF SNPs rs208294 (His155Tyr) and rs1718119 (Ala348Thr) is associated, in females, with higher pain intensity scores.ConclusionsOur present results confirm the physiological relevance of some of the SNPs in the P2RX7 gene and show that the presence of these genetic variants correlates with pain sensitivity also in a diabetic neuropathic pain patient population.

Genes Associated with Increased Fasting Glucose in Patients with Schizophrenia Spectrum Disorders

“…In support of our finding, the allele G of the non-synonymous variation rs1718119 showed a gain-offunction phenotype, and fibroblasts from type 2 diabetes patients are characterized by increased purinergic activity [59,60].…”

P2X ion channel receptors and inflammation

“…The NLRP3 inflammasome is a central mediator of systemic inflammation and a link between psychological stress and the emergence of depression and other psychiatric illnesses [118] and ATP, accumulated following insult, induces NLRPmediated IL-1β processing [93]. Epidemiological and genelinking studies have implicated P2X7 in a host of CNS diseases [119,120]. Neuroimmunological changes occur in psychiatric disorders, including major depressive disorder, bipolar disorder, obsessive compulsive disorder, and schizophrenia.…”

Purinergic P2X7 receptor functional genetic polymorphisms are associated with the susceptibility to osteoporosis in Chinese postmenopausal women

“…Fourthly, mutations of rs7958311 could also alter coding of amino acids (His357 to Arg) and was associated with a partial function loss of P2X7R through affecting channel and pore function [22,23]. Rs7958311 was shown to be related with many disorders, including pulmonary tuberculosis, chronic pain, and anxiety [21,28,29]. However, the rs7958311 variant investigated in the present study was not associated with risk of OP.…”

“…For example, three P2X7R SNPs with amino acid changes, rs3751143 (1513A > C, Glu496Ala), rs2230911 (1096 C > G, Thr357Ser), and rs7958311 (835G > A, Arg270His), were shown to lead to a loss of receptor function in both channel and pore function [22,23]. Rs3751143 and rs2230911 were reported to be associated with a higher prevalence of OP [25][26][27], while rs7958311 was shown to be related with other diseases, including pulmonary tuberculosis, chronic pain, and anxiety [21,28,29]. On the other hand, the polymorphism of rs1718119 (1068G > A, Ala348Thr) causes a gain of function of the receptor via regulating channel and pore function [30].…”