Transmembrane Prolyl 4-Hydroxylase is a Novel Regulator of Calcium Signaling in Astrocytes

Nadiya Byts; Subodh Sharma; Jenny Laurila; Prodeep Paudel; Ilkka Miinalainen; Veli-Pekka Ronkainen; Reetta Hinttala; Kid Törnquist; Peppi Koivunen; Johanna Myllyharju

doi:10.1523/ENEURO.0253-20.2020

Transmembrane Prolyl 4-Hydroxylase is a Novel Regulator of Calcium Signaling in Astrocytes

eNeuro. 2021 Jan 8;8(1):ENEURO.0253-20.2020. doi: 10.1523/ENEURO.0253-20.2020. Print 2021 Jan-Feb.

Authors

Affiliations

¹ Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu 90014, Finland.
² Biocenter Oulu, University of Oulu, Oulu 90014, Finland.
³ PEDEGO Research Unit, Faculty of Medicine, University of Oulu, Oulu 90014, Finland.
⁴ Cell Biology, Faculty of Science and Engineering, Åbo Akademi University, Turku 20500, Finland.
⁵ Minerva Foundation Institute for Medical Research, Biomedicum Helsinki, Helsinki 00290, Finland.
⁶ Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu 90014, Finland johanna.myllyharju@oulu.fi.

Abstract

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.

Keywords: calcium signaling; hypoxia-inducible factor; prolyl 4-hydroxylase; vesicular exocytosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Astrocytes* / metabolism
Calcium Signaling*
Humans
Hypoxia
Procollagen-Proline Dioxygenase / metabolism
Prolyl Hydroxylases

Substances

Prolyl Hydroxylases
Procollagen-Proline Dioxygenase