Transmembrane prolyl 4-hydroxylase is a novel regulator of calcium signaling in astrocytes
Byts, Nadiya; Sharma, Subodh; Laurila, Jenny; Paudel, Prodeep; Miinalainen, Ilkka; Ronkainen, Veli-Pekka; Hinttala, Reetta; Törnquist, Kid; Koivunen, Peppi; Myllyharju, Johanna (2020-12-09)
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
© 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.
https://creativecommons.org/licenses/by/4.0/
https://urn.fi/URN:NBN:fi-fe202102235709
Tiivistelmä
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.
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