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Purinergic Pharmacology

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Front. Pharmacol. | doi: 10.3389/fphar.2018.00170

Haploinsufficient TNAP Mice Display Decreased Extracellular ATP Levels and Expression of Pannexin-1 Channels

 Álvaro Sebastian-Serrano1, 2, Laura de Diego-García1, 2,  David Henshall3, 4,  Tobias Engel3, 4 and  Miguel Diaz-Hernandez1, 2*
  • 1Biochemistry and molecular biology, Complutense University of Madrid, Spain
  • 2Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Spain
  • 3Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Ireland
  • 4FutureNeuro Research Centre, Science Foundation Ireland, Ireland

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 (CSF), 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 (VNUT). 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.

Keywords: Tissue-nonspecific alkaline phosphatase (TNAP), Adenosine 5´- triphosphate (ATP), Hypophosphatasia (HPP), P2X7 receptor (P2X7R), pannexin 1 (Panx1), seizure, Epilepsy, Connexins

Received: 15 Oct 2017; Accepted: 15 Feb 2018.

Edited by:

Francisco Ciruela, Universitat de Barcelona, Spain

Reviewed by:

Nathalie Rouach, Collège de France, France
Michael F. Jackson, University of Manitoba, Canada  

Copyright: © 2018 Sebastian-Serrano, de Diego-García, Henshall, Engel and Diaz-Hernandez. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Miguel Diaz-Hernandez, Complutense University of Madrid, Biochemistry and molecular biology, Madrid, 28040, Madrid, Spain,