University of Oulu

Nadiya Byts, Subodh Sharma, Jenny Laurila, Prodeep Paudel, Ilkka Miinalainen, Veli-Pekka Ronkainen, Reetta Hinttala, Kid Törnquist, Peppi Koivunen, Johanna Myllyharju (2020) Transmembrane Prolyl 4-Hydroxylase is a Novel Regulator of Calcium Signaling in Astrocytes. eNeuro 9 December 2020, 8 (1) ENEURO.0253-20.2020; DOI: 10.1523/ENEURO.0253-20.2020

Transmembrane prolyl 4-hydroxylase is a novel regulator of calcium signaling in astrocytes

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Author: Byts, Nadiya1; Sharma, Subodh1; Laurila, Jenny1;
Organizations: 1Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu 90014, Finland
2Biocenter Oulu, University of Oulu, Oulu 90014, Finland
3PEDEGO Research Unit, Faculty of Medicine, University of Oulu, Oulu 90014, Finland
4Cell Biology, Faculty of Science and Engineering, Åbo Akademi University, Turku 20500, Finland
5Minerva Foundation Institute for Medical Research, Biomedicum Helsinki, Helsinki 00290, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.8 MB)
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Language: English
Published: Society for Neuroscience, 2020
Publish Date: 2021-02-23


Prolyl 4-hydroxylases (P4Hs) have vital roles in regulating collagen synthesis and hypoxia response. A transmembrane P4H (P4H-TM) is a recently identified member of the family. Biallelic loss of function P4H-TM mutations cause a severe autosomal recessive intellectual disability syndrome in humans, but functions of P4H-TM are essentially unknown at cellular level. Our microarray data on P4h-tm−/− mouse cortexes where P4H-TM is abundantly expressed indicated expression changes in genes involved in calcium signaling and expression of several calcium sequestering ATPases was upregulated in P4h-tm−/− primary mouse astrocytes. Cytosolic and intraorganellar calcium imaging of P4h-tm−/− cells revealed that receptor-operated calcium entry (ROCE) and store-operated calcium entry (SOCE) and calcium re-uptake by mitochondria were compromised. HIF1, but not HIF2, was found to be a key mediator of the P4H-TM effect on calcium signaling. Furthermore, total internal reflection fluorescence (TIRF) imaging showed that calcium agonist-induced gliotransmission was attenuated in P4h-tm−/− astrocytes. This phenotype was accompanied by redistribution of mitochondria from distal processes to central parts of the cell body and decreased intracellular ATP content. Our data show that P4H-TM is a novel regulator of calcium dynamics and gliotransmission.

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Series: eNeuro
ISSN: 2373-2822
ISSN-E: 2373-2822
ISSN-L: 2373-2822
Volume: 8
Issue: 1
Pages: 1 - 23
Article number: ENEURO.0253-20.2020
DOI: 10.1523/ENEURO.0253-20.2020
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
1182 Biochemistry, cell and molecular biology
Funding: This work was supported by Academy of Finland Project Grants 296498 (to J.M.) and 266719 and 308009 (to P.K.), the Academy of Finland Center of Excellence 2012-2017 Grant 251314 (to J.M.), the S. Jusélius Foundation (J.M., P.K.), the Jane and Aatos Erkko Foundation (J.M., P.K.), and FibroGen Inc. (J.M.).
Academy of Finland Grant Number: 296498
Detailed Information: 296498 (Academy of Finland Funding decision)
266719 (Academy of Finland Funding decision)
308009 (Academy of Finland Funding decision)
251314 (Academy of Finland Funding decision)
Copyright information: © 2020 Byts et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.