Journal
FEBS LETTERS
Volume 595, Issue 22, Pages 2756-2767Publisher
WILEY
DOI: 10.1002/1873-3468.14213
Keywords
calcium transport; forskolin; metabolism; obesity; sarcolipin; sarcoplasmic reticulum
Funding
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- NSERC
- Ontario Graduate Scholarship in Science and Technology (OGS)
- OGS
- NSERC Discovery Research grant [RGPIN 2019-05833]
- Brock Explore Grant
- Canada Research Chair (Tier II)
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NNAT acts as a SERCA uncoupler by reducing Ca2+ uptake, potentially playing a role in adaptive thermogenesis.
Neuronatin (NNAT) is a transmembrane protein in the endoplasmic reticulum involved in metabolic regulation. It shares sequence homology with sarcolipin (SLN), which negatively regulates the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) that maintains energy homeostasis in muscles. Here, we examined whether NNAT could uncouple the Ca2+ transport activity of SERCA from ATP hydrolysis, similarly to SLN. NNAT significantly reduced Ca2+ uptake without altering SERCA activity, ultimately lowering the apparent coupling ratio of SERCA. This effect of NNAT was reversed by the adenylyl cyclase activator forskolin. Furthermore, soleus muscles from high fat diet (HFD)-fed mice showed a significant downregulation in NNAT content compared with chow-fed mice, whereas an upregulation in NNAT content was observed in fast-twitch muscles from HFD- versus chow- fed mice. Therefore, NNAT is a SERCA uncoupler in cells and may function in adaptive thermogenesis.
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