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

eNeuro 2021 Jan-Feb

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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. Copyright © 2021 Byts et al.

Citation

Nadiya Byts, Subodh Sharma, Jenny Laurila, Prodeep Paudel, Ilkka Miinalainen, Veli-Pekka Ronkainen, Reetta Hinttala, Kid Törnquist, Peppi Koivunen, Johanna Myllyharju. Transmembrane Prolyl 4-Hydroxylase is a Novel Regulator of Calcium Signaling in Astrocytes. eNeuro. 2021 Jan-Feb;8(1)