Gain and loss of function of $ P2X_{7} $ receptors: mechanisms, pharmacology and relevance to diabetic neuropathic pain
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 $ P2X_{7,} $ 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 $ P2X_{7} $ and actual channel protein expression. Both channel and pore function for these mutant $ P2X_{7} $ receptors changed in parallel to protein levels. On the other hand, the mutant receptors did not differ in their sensitivity to known $ P2X_{7} $ 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..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2014 |
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| Erschienen: |
2014 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
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| Enthalten in: |
Molecular pain - 10(2014), 1 vom: 16. Juni |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ursu, Daniel [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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| Themen: |
Gain-of-function |
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| Anmerkungen: |
© Ursu et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( |
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| doi: |
10.1186/1744-8069-10-37 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a 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 $ P2X_{7,} $ 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 $ P2X_{7} $ and actual channel protein expression. Both channel and pore function for these mutant $ P2X_{7} $ receptors changed in parallel to protein levels. On the other hand, the mutant receptors did not differ in their sensitivity to known $ P2X_{7} $ 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. | ||
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