期刊
ENEURO
卷 8, 期 1, 页码 -出版社
SOC NEUROSCIENCE
DOI: 10.1523/ENEURO.0253-20.2020
关键词
calcium signaling; hypoxia-inducible factor; prolyl 4-hydroxylase; vesicular exocytosis
资金
- Academy of Finland [296498, 266719, 308009]
- Academy of Finland Center of Excellence [251314]
- S. Juselius Foundation
- Jane and Aatos Erkko Foundation
- FibroGen Inc.
- Academy of Finland (AKA) [296498, 296498, 266719] Funding Source: Academy of Finland (AKA)
Prolyl 4-hydroxylases (P4Hs) are crucial in regulating collagen synthesis and response to hypoxia. A newly identified member, transmembrane P4H (P4H-TM), plays a key role in calcium signaling and gliotransmission regulation. Loss of function mutations in P4H-TM can lead to severe intellectual disability syndrome.
Prolyl 4-hydroxylases (P4Hs) have vital roles in regulating collagen synthesis and hypoxia response. A trans membrane 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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