title: Gain and loss of function of P2X7 receptors: mechanisms, pharmacology and relevance to diabetic neuropathic pain.
abstract: BACKGROUND
  Genetic 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  Our 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.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ursu
authors.forename: Philip
authors.initials: P
authors.lastname: Ebert
authors.forename: Emily
authors.initials: E
authors.lastname: Langron
authors.forename: Cara
authors.initials: C
authors.lastname: Ruble
authors.forename: Leanne
authors.initials: L
authors.lastname: Munsie
authors.forename: Wei
authors.initials: W
authors.lastname: Zou
authors.forename: Bonnie
authors.initials: B
authors.lastname: Fijal
authors.forename: Yue-Wei
authors.initials: YW
authors.lastname: Qian
authors.forename: Terry A
authors.initials: TA
authors.lastname: McNearney
authors.forename: Adrian
authors.initials: A
authors.lastname: Mogg
authors.forename: Olivera
authors.initials: O
authors.lastname: Grubisha
authors.forename: Kalpana
authors.initials: K
authors.lastname: Merchant
authors.affiliation: Lilly Research Centre, Eli Lilly & Co, Ltd,, Sunninghill Road, GU20 6PH Windlesham, Surrey, UK. sher_emanuele@lilly.com.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Sher
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000704:Analysis of Variance; D001583:Benzoxazoles / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003929:Diabetic Neuropathies / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D010147:Pain Measurement; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D011806:Quinolinium Compounds / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000235:genetics*; D014162:Transfection
chemical_list: D001583:Benzoxazoles; D010975:Platelet Aggregation Inhibitors; D058920:Purinergic P2X Receptor Antagonists; D011806:Quinolinium Compounds; D058486:Receptors, Purinergic P2X7; C089813:YO-PRO 1; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate; D002118:Calcium