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- W4387432830 abstract "Abstract Acid‐sensing ion channels (ASICs) are important players in detecting extracellular acidification throughout the brain and body. ASICs have large extracellular domains containing two regions replete with acidic residues: the acidic pocket and the palm domain. In the resting state, the acidic pocket is in an expanded conformation but collapses in low pH conditions as the acidic side chains are neutralized. Thus, extracellular acidification has been hypothesized to collapse the acidic pocket that, in turn, ultimately drives channel activation. However, several observations run counter to this idea. To explore how collapse or mobility of the acidic pocket is linked to channel gating, we employed two distinct tools. First, we incorporated the photocrosslinkable non‐canonical amino acids (ncAAs) AzF or BzF into several positions in the acidic pocket. At both E315 and Y318, AzF incorporation followed by UV irradiation led to right shifts in pH response curves and accelerations of desensitization and deactivation, consistent with restrictions of acidic pocket mobility destabilizing the open state. Second, we reasoned that because Cl ‐ ions are found in the open and desensitized structures but absent in the resting state structures, Cl ‐ substitution would provide insight into how stability of the pocket is linked to gating. Anion substitution resulted in faster deactivation and desensitization, consistent with the acidic pocket regulating the stability of the open state. Taken together, our data support a model where acidic pocket collapse is not essential for channel activation. Rather, collapse of the acidic pocket influences the stability of the open state of the pore. This article is protected by copyright. All rights reserved." @default.
- W4387432830 created "2023-10-09" @default.
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- W4387432830 date "2023-10-08" @default.
- W4387432830 modified "2023-10-10" @default.
- W4387432830 title "Photomodulation of the <scp>ASIC1a</scp> acidic pocket destabilizes the open state" @default.
- W4387432830 doi "https://doi.org/10.1002/pro.4800" @default.
- W4387432830 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37805833" @default.
- W4387432830 hasPublicationYear "2023" @default.
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