RT Journal Article
T1 Haploinsufficient TNAP Mice Display Decreased Extracellular ATP Levels and Expression of Pannexin-1 Channels
A1 Sebastián Serrano, Álvaro
A1 De Diego García, Laura
A1 Engel, Tobias
A1 Henshall, DC
A1 Díaz Hernández, Miguel
AB 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.
PB Frontiers Media
YR 2018
FD 2018-03-02
LK https://hdl.handle.net/20.500.14352/114537
UL https://hdl.handle.net/20.500.14352/114537
LA eng
NO Sebastián-Serrano, Á., de Diego-García, L., Henshall, D. C., Engel, T., & Díaz-Hernández, M. (2018). Haploinsufficient TNAP Mice Display Decreased Extracellular ATP Levels and Expression of Pannexin-1 Channels. Frontiers in pharmacology, 9, 170. https://doi.org/10.3389/fphar.2018.00170
NO Author contributions:ÁS-S prepared protein extract, realized Western blot, immunohistochemistry, TNAP activity test, RT-qPCRs, ATP measurement, participated in experimental design, in the interpretation of the work and wrote the manuscript. LdD-G performed Western blot of hemichannels, ecto-ATPase activity assay, and revised the manuscript. TE performed in vivo seizure induction and recording and revised the manuscript. DH revised the manuscript. MD-H performed CSF acquisition and ATP measurement, participated in the experimental design, in the interpretation of the results, wrote the manuscript and also provided the financial support for the work.
NO Ministerio de Ciencia, Innovación y Universidades (España)
NO European Commission
NO Universidad Complutense de Madrid
NO Banco Santander Central Hispano
NO Science Foundation Ireland
DS Docta Complutense
RD 20 abr 2025