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Gain and loss of function of P2X7 receptors: mechanisms, pharmacology and relevance to diabetic neuropathic pain.
Mol Pain. 2014 Jun 16; 10:37.MP

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+Show Affiliations

No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableLilly Research Centre, Eli Lilly & Co, Ltd,, Sunninghill Road, GU20 6PH Windlesham, Surrey, UK. sher_emanuele@lilly.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24934217

Citation

Ursu, Daniel, et al. "Gain and Loss of Function of P2X7 Receptors: Mechanisms, Pharmacology and Relevance to Diabetic Neuropathic Pain." Molecular Pain, vol. 10, 2014, p. 37.
Ursu D, Ebert P, Langron E, et al. Gain and loss of function of P2X7 receptors: mechanisms, pharmacology and relevance to diabetic neuropathic pain. Mol Pain. 2014;10:37.
Ursu, D., Ebert, P., Langron, E., Ruble, C., Munsie, L., Zou, W., Fijal, B., Qian, Y. W., McNearney, T. A., Mogg, A., Grubisha, O., Merchant, K., & Sher, E. (2014). Gain and loss of function of P2X7 receptors: mechanisms, pharmacology and relevance to diabetic neuropathic pain. Molecular Pain, 10, 37. https://doi.org/10.1186/1744-8069-10-37
Ursu D, et al. Gain and Loss of Function of P2X7 Receptors: Mechanisms, Pharmacology and Relevance to Diabetic Neuropathic Pain. Mol Pain. 2014 Jun 16;10:37. PubMed PMID: 24934217.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Gain and loss of function of P2X7 receptors: mechanisms, pharmacology and relevance to diabetic neuropathic pain. AU - Ursu,Daniel, AU - Ebert,Philip, AU - Langron,Emily, AU - Ruble,Cara, AU - Munsie,Leanne, AU - Zou,Wei, AU - Fijal,Bonnie, AU - Qian,Yue-Wei, AU - McNearney,Terry A, AU - Mogg,Adrian, AU - Grubisha,Olivera, AU - Merchant,Kalpana, AU - Sher,Emanuele, Y1 - 2014/06/16/ PY - 2014/02/18/received PY - 2014/06/09/accepted PY - 2014/6/18/entrez PY - 2014/6/18/pubmed PY - 2014/10/18/medline SP - 37 EP - 37 JF - Molecular pain JO - Mol Pain VL - 10 N2 - 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. SN - 1744-8069 UR - https://www.unboundmedicine.com/medline/citation/24934217/Gain_and_loss_of_function_of_P2X7_receptors:_mechanisms_pharmacology_and_relevance_to_diabetic_neuropathic_pain_ L2 - http://journals.sagepub.com/doi/full/10.1186/1744-8069-10-37?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -