Journal
ELIFE
Volume 11, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.82955
Keywords
chloride channel; desensitization; inactivation; PAC; TMEM206; ASOR; Human
Categories
Funding
- American Heart Association (AHA) [18PRE34060025]
- AHA postdoctoral fellowship [20POST35120556]
- National Institute of Health [K99NS128258]
- National Institute of General Medical Sciences [T32 GM007445]
- Physician Scientist Training Program grant from Johns Hopkins University School of Medicine
- National Institute of Health (NIH) [R01NS112363, R35GM124824, R01NS118014]
- McKnight Scholar Award
- Klingenstein-Simon Scholar Award
- Sloan Research Fellowship in Neuroscience
- Boehringer Ingelheim Fonds (BIF)
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In this study, it was found that the newly identified PAC channel undergoes pH-dependent desensitization upon prolonged acid exposure. Several critical residues at the TM1 extension and the ECD-TMD interface were identified to play important roles in PAC desensitization. Structural analysis and molecular dynamic simulations revealed the extensive interactions between residues at the TM1 extension and those at the ECD-TMD interface, which likely facilitate PAC desensitization by stabilizing the desensitized conformation of TM1.
Desensitization is a common property of membrane receptors, including ion channels. The newly identified proton-activated chloride (PAC) channel plays an important role in regulating the pH and size of organelles in the endocytic pathway, and is also involved in acid-induced cell death. However, how the PAC channel desensitizes is largely unknown. Here, we show by patch-clamp electrophysiological studies that PAC (also known as TMEM206/ASOR) undergoes pH-dependent desensitization upon prolonged acid exposure. Through structure-guided and comprehensive mutagenesis, we identified several residues critical for PAC desensitization, including histidine (H) 98, glutamic acid (E) 94, and aspartic acid (D) 91 at the extracellular extension of the transmembrane helix 1 (TM1), as well as E107, D109, and E250 at the extracellular domain (ECD)-transmembrane domain (TMD) interface. Structural analysis and molecular dynamic simulations revealed extensive interactions between residues at the TM1 extension and those at the ECD-TMD interface. These interactions likely facilitate PAC desensitization by stabilizing the desensitized conformation of TM1, which undergoes a characteristic rotational movement from the resting and activated states to the desensitized state. Our studies establish a new paradigm of channel desensitization in this ubiquitously expressed ion channel and pave the way for future investigation of its relevance in cellular physiology and disease.
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