Of critical physiological importance, ASIC1a has a clearly demonstrated role in cell death resulting from ischemic stroke ( Gao et al., 2005 Wang et al., 2020 Wang et al., 2015). Moreover, mutations and truncations in the termini have been shown to impact channel gating as well ( Li et al., 2021). These proteins can influence trafficking, gating, and localization. ASICs have been shown to interact with a wide variety of intracellular proteins ( Cullinan et al., 2021) like stomatin ( Brand et al., 2012 Klipp et al., 2020 Price et al., 2004), NHERF ( Deval et al., 2006), and CIPP ( Anzai et al., 2002). It is likely these domains are highly dynamic and largely unstructured.ĭespite the lack of structure, the termini play a critical role in channel function and regulation. Nonetheless, the C-terminus and the cytosolic portion of the N-terminus remain unresolved. More recent structures of cASIC1 from the same group using CryoEM on channels solubilized with styrene-maleic acid copolymer revealed that residues 19–41 reenter the membrane and form part of the lower permeation path: a feature that was termed the re-entrant loop ( Yoder and Gouaux, 2020). A single subunit of cASIC1 is comprised of a large cysteine-rich extracellular domain, two transmembrane domains and short intracellular N- and C-termini. The first structure of a member of this family, ASIC1 from chicken (cASIC1), was solved at 1.9 Å and revealed the overall architecture of the channel ( Jasti et al., 2007). ASICs have been shown to be involved in diverse physiological and pathophysiological conditions including pain sensing ( Bässler et al., 2001 Mazzuca et al., 2007 Sluka et al., 2009), mechanotransduction ( Hermanstyne et al., 2008), fear conditioning ( Coryell et al., 2008 Du et al., 2014), and memory and learning ( Wemmie et al., 2002). In mammals, there are four ASIC genes giving rise to six unique isoforms that can assemble into homo- and heteromeric channels. ASICs are trimeric, proton activated, sodium selective channels located primarily in the central and peripheral nervous systems. melanogaster and most recently identified, the heat-activated BRNTaC1 from S.s mutilans ( Yao et al., 2023). eLife assessmentĪcid-sensing ion channels (ASICs) are members of the Deg/ENaC (Degenerin/Epithelial Sodium Channel) superfamily, with relatives including the mechanosensitive MEC4 from C. Together these data suggest that a new hypothesis for RIPK1 binding during stroke is needed. After acidification, the proximal portion of the N-terminus moves marginally closer to the membrane whereas the distal portion of the C-terminus swings away from the membrane. The distal end of the C-terminus may also spend time close to the membrane at rest. At rest, the N-terminus adopts a conformation parallel to the membrane about 10 Å away. We do not find evidence that the termini are close enough to be bound while the channel is at rest and find that the termini may modestly move closer together during acidification. Here, we use two transition metal ion FRET methods to investigate the conformational dynamics of the termini at neutral and acidic pH. This interaction is hypothesized to be inhibited at rest via an interaction between the C- and N-termini which blocks the RIPK1 binding site. The C-terminus of ASIC1a is thought to mediate necroptotic cell death through interaction with receptor interacting serine threonine kinase 1 (RIPK1). Recent work has shown that these channels play a role in necroptosis following prolonged acidic exposure like occurs in stroke. Acid-sensing ion channels (ASICs) are trimeric proton-gated sodium channels.
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