- TMEM63B is a dual-function TCS protein acting as mechanosensitive and osmosensitive ion channel and lipid scramblase.
- Recent structures reveal distinct channel and scramblase conformations and activation mechanisms underpinning gating and lipid translocation.
- Broad tissue distribution and disease-linked mutations highlight physiological importance and pharmacological potential for isoform-selective modulators and biologics such as antibody YN9303-24.
Biochem Pharmacol. 2026 Oct 29:118582. doi: 10.1016/j.bcp.2026.118582. Online ahead of print.
ABSTRACT
TMEM63B, a member of the transmembrane channel/scramblase (TCS) superfamily, functions as both a mechanosensitive and osmosensitive ion channel and a lipid scramblase. Recent structural and functional studies have begun to reveal the molecular basis underlying these dual functions. In this review, we summarize the current understanding of TMEM63B, focusing on its structural architecture, channel and scramblase conformations, activation mechanisms, physiological roles and therapeutic potential. Importantly, the broad tissue distribution and disease-associated mutations of TMEM63B-linked to developmental epileptic encephalopathy, hemolytic anemia, placental dysfunction, pulmonary insufficiency, and intestinal barrier defects-underscore its emerging pharmacological relevance. We discuss the therapeutic opportunities and challenges in targeting TMEM63B, including allosteric modulation of its mechanosensitive gating, isoform- and tissue-selective strategies to mitigate on-target off-tissue toxicity, and the potential of biologics such as the agonistic antibody YN9303-24 for loss-of-function disorders. These insights provide a framework for understanding the mechanistic diversity of TCS proteins, their physiological significance, and their translational potential as a new class of druggable mechanosensitive targets.
PMID:42957056 | DOI:10.1016/j.bcp.2026.118582
Share Evidence Blueprint
Save to Google Notes
Search Google Scholar
Save as PDF
⭐ My Revision List
