Haploinsufficient TNAP Mice Display Decreased Extracellular ATP Levels and Expression of Pannexin-1 Channels
Hypophosphatasia (HPP) is a rare heritable metabolic bone disease caused by hypomorphic mutations in the ALPL (in human) or Akp2 (in mouse) gene, encoding the tissue-nonspecific alkaline phosphatase (TNAP) enzyme. In addition to skeletal and dental malformations, severe forms of HPP are also charact...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fphar.2018.00170/full |
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| author | Álvaro Sebastián-Serrano Álvaro Sebastián-Serrano Laura de Diego-García Laura de Diego-García David C. Henshall David C. Henshall Tobías Engel Tobías Engel Miguel Díaz-Hernández Miguel Díaz-Hernández |
| author_facet | Álvaro Sebastián-Serrano Álvaro Sebastián-Serrano Laura de Diego-García Laura de Diego-García David C. Henshall David C. Henshall Tobías Engel Tobías Engel Miguel Díaz-Hernández Miguel Díaz-Hernández |
| author_sort | Álvaro Sebastián-Serrano |
| collection | DOAJ |
| description | Hypophosphatasia (HPP) is a rare heritable metabolic bone disease caused by hypomorphic mutations in the ALPL (in human) or Akp2 (in mouse) gene, encoding the tissue-nonspecific alkaline phosphatase (TNAP) enzyme. In addition to skeletal and dental malformations, severe forms of HPP are also characterized by the presence of spontaneous seizures. Initially, these seizures were attributed to an impairment of GABAergic neurotransmission caused by altered vitamin B6 metabolism. However, recent work by our group using knockout mice null for TNAP (TNAP-/-), a well-described model of infantile HPP, has revealed a deregulation of purinergic signaling contributing to the seizure phenotype. In the present study, we report that adult heterozygous (TNAP+/-) transgenic mice with decreased TNAP activity in the brain are more susceptible to adenosine 5′-triphosphate (ATP)-induced seizures. Interestingly, when we analyzed the extracellular levels of ATP in the cerebrospinal fluid, we found that TNAP+/- mice present lower levels than control mice. To elucidate the underlying mechanism, we evaluated the expression levels of other ectonucleotidases, as well as different proteins involved in ATP release, such as pannexin, connexins, and vesicular nucleotide transporter. Among these, Pannexin-1 (Panx1) was the only one showing diminished levels in the brains of TNAP+/- mice. Altogether, these findings suggest that a physiological regulation of extracellular ATP levels and Panx1 changes may compensate for the reduced TNAP activity in this model of HPP. |
| first_indexed | 2024-12-21T02:34:25Z |
| format | Article |
| id | doaj.art-a912931503f949ce9f9342273387f977 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-21T02:34:25Z |
| publishDate | 2018-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-a912931503f949ce9f9342273387f9772022-12-21T19:18:50ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-03-01910.3389/fphar.2018.00170320498Haploinsufficient TNAP Mice Display Decreased Extracellular ATP Levels and Expression of Pannexin-1 ChannelsÁlvaro Sebastián-Serrano0Álvaro Sebastián-Serrano1Laura de Diego-García2Laura de Diego-García3David C. Henshall4David C. Henshall5Tobías Engel6Tobías Engel7Miguel Díaz-Hernández8Miguel Díaz-Hernández9Department of Biochemistry and Molecular Biology, Veterinary School, Complutense University of Madrid, Madrid, SpainInstituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, SpainDepartment of Biochemistry and Molecular Biology, Veterinary School, Complutense University of Madrid, Madrid, SpainInstituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, SpainDepartment of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, IrelandFutureNeuro Research Centre, Dublin, IrelandDepartment of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, IrelandFutureNeuro Research Centre, Dublin, IrelandDepartment of Biochemistry and Molecular Biology, Veterinary School, Complutense University of Madrid, Madrid, SpainInstituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, SpainHypophosphatasia (HPP) is a rare heritable metabolic bone disease caused by hypomorphic mutations in the ALPL (in human) or Akp2 (in mouse) gene, encoding the tissue-nonspecific alkaline phosphatase (TNAP) enzyme. In addition to skeletal and dental malformations, severe forms of HPP are also characterized by the presence of spontaneous seizures. Initially, these seizures were attributed to an impairment of GABAergic neurotransmission caused by altered vitamin B6 metabolism. However, recent work by our group using knockout mice null for TNAP (TNAP-/-), a well-described model of infantile HPP, has revealed a deregulation of purinergic signaling contributing to the seizure phenotype. In the present study, we report that adult heterozygous (TNAP+/-) transgenic mice with decreased TNAP activity in the brain are more susceptible to adenosine 5′-triphosphate (ATP)-induced seizures. Interestingly, when we analyzed the extracellular levels of ATP in the cerebrospinal fluid, we found that TNAP+/- mice present lower levels than control mice. To elucidate the underlying mechanism, we evaluated the expression levels of other ectonucleotidases, as well as different proteins involved in ATP release, such as pannexin, connexins, and vesicular nucleotide transporter. Among these, Pannexin-1 (Panx1) was the only one showing diminished levels in the brains of TNAP+/- mice. Altogether, these findings suggest that a physiological regulation of extracellular ATP levels and Panx1 changes may compensate for the reduced TNAP activity in this model of HPP.http://journal.frontiersin.org/article/10.3389/fphar.2018.00170/fulltissue-nonspecific alkaline phosphatase (TNAP)adenosine 5′-triphosphate (ATP)hypophosphatasia (HPP)P2X7 receptor (P2X7R)pannexin 1 (Panx1)seizure |
| spellingShingle | Álvaro Sebastián-Serrano Álvaro Sebastián-Serrano Laura de Diego-García Laura de Diego-García David C. Henshall David C. Henshall Tobías Engel Tobías Engel Miguel Díaz-Hernández Miguel Díaz-Hernández Haploinsufficient TNAP Mice Display Decreased Extracellular ATP Levels and Expression of Pannexin-1 Channels Frontiers in Pharmacology tissue-nonspecific alkaline phosphatase (TNAP) adenosine 5′-triphosphate (ATP) hypophosphatasia (HPP) P2X7 receptor (P2X7R) pannexin 1 (Panx1) seizure |
| title | Haploinsufficient TNAP Mice Display Decreased Extracellular ATP Levels and Expression of Pannexin-1 Channels |
| title_full | Haploinsufficient TNAP Mice Display Decreased Extracellular ATP Levels and Expression of Pannexin-1 Channels |
| title_fullStr | Haploinsufficient TNAP Mice Display Decreased Extracellular ATP Levels and Expression of Pannexin-1 Channels |
| title_full_unstemmed | Haploinsufficient TNAP Mice Display Decreased Extracellular ATP Levels and Expression of Pannexin-1 Channels |
| title_short | Haploinsufficient TNAP Mice Display Decreased Extracellular ATP Levels and Expression of Pannexin-1 Channels |
| title_sort | haploinsufficient tnap mice display decreased extracellular atp levels and expression of pannexin 1 channels |
| topic | tissue-nonspecific alkaline phosphatase (TNAP) adenosine 5′-triphosphate (ATP) hypophosphatasia (HPP) P2X7 receptor (P2X7R) pannexin 1 (Panx1) seizure |
| url | http://journal.frontiersin.org/article/10.3389/fphar.2018.00170/full |
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