Tao Ran, Robertson Alan D, Fuller William, Gök Caglar
School of Cardiovascular and Metabolic Health, Sir James Black Building, University of Glasgow, Glasgow, G12 8QQ, U.K.
School of Natural Sciences, College of Health and Science, University of Lincoln, Lincoln, LN6 7TS, U.K.
Biosci Rep. 2025 Jan 30;45(1):1-11. doi: 10.1042/BSR20241051.
Cellular Ca2+ homeostasis is critical for normal cell physiology and is regulated by several mechanisms. Two major players in intracellular Ca2+ homeostasis in multiple tissues belong to the SLC8 (Na+/Ca2+ exchangers (NCXs); NCX1-3) and SLC24 (K+ dependent Na+/Ca2+ exchangers (NCKXs); NCKX1-5) families. It has been established that NCXs and NCKX4 are palmitoylated, and that palmitoylation promotes NCX1 inactivation. However, there is still little known about NCKXs' palmitoylation. We found that (1) NCKX3 and NCKX5, but not NCKX1, are palmitoylated, (2) Cys to Ala mutation at position 467 for NCXK3 and 325 for NCKX5 notably diminished palmitoylation and (3) reduced palmitoylation enhanced NCKX3 activity. Our findings bring novel insights into NCKX1, NCKX3 and NCKX5 palmitoylation and establish palmitoylation as an endogenous regulator of NCKX3 activity, paving the way for investigations evaluating the role of palmitoylation in NCKX3 function in health and disease.
细胞内钙离子稳态对于正常细胞生理功能至关重要，且受多种机制调控。多种组织中细胞内钙离子稳态的两个主要参与者属于SLC8（钠/钙交换体（NCXs）；NCX1 - 3）和SLC24（钾依赖性钠/钙交换体（NCKXs）；NCKX1 - 5）家族。已证实NCXs和NCKX4发生棕榈酰化，且棕榈酰化促进NCX1失活。然而，关于NCKXs的棕榈酰化仍知之甚少。我们发现：（1）NCKX3和NCKX5发生棕榈酰化，而NCKX1未发生；（2）NCXK3第467位和NCKX5第325位的半胱氨酸突变为丙氨酸显著减少了棕榈酰化；（3）棕榈酰化减少增强了NCKX3活性。我们的研究结果为NCKX1、NCKX3和NCKX5的棕榈酰化带来了新见解，并确立了棕榈酰化作为NCKX3活性的内源性调节剂，为评估棕榈酰化在健康和疾病中NCKX3功能的作用的研究铺平了道路。
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