International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na<sup>+</sup>Channel

Kellenberger, Stephan; Schild, Laurent

doi:10.1124/pr.114.009225

Cited by 248 publications

(346 citation statements)

References 332 publications

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“…ASICs are involved in fear behaviors, learning, neurodegeneration after ischemic stroke, and pain sensation (2,3). Functional ASICs are composed of three identical or homologous subunits (4,5).…”

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confidence: 99%

Conformational dynamics and role of the acidic pocket in ASIC pH-dependent gating

Vullo

Bonifacio

Roy

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Acid-sensing ion channels (ASICs) are proton-activated Na + channels expressed in the nervous system, where they are involved in learning, fear behaviors, neurodegeneration, and pain sensation. In this work, we study the role in pH sensing of two regions of the ectodomain enriched in acidic residues: the acidic pocket, which faces the outside of the protein and is the binding site of several animal toxins, and the palm, a central channel domain. Using voltage clamp fluorometry, we find that the acidic pocket undergoes conformational changes during both activation and desensitization. Concurrently, we find that, although proton sensing in the acidic pocket is not required for channel function, it does contribute to both activation and desensitization. Furthermore, protonationmimicking mutations of acidic residues in the palm induce a dramatic acceleration of desensitization followed by the appearance of a sustained current. In summary, this work describes the roles of potential pH sensors in two extracellular domains, and it proposes a model of acidification-induced conformational changes occurring in the acidic pocket of ASIC1a.

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confidence: 99%

Conformational dynamics and role of the acidic pocket in ASIC pH-dependent gating

Vullo

Bonifacio

Roy

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…1). Of the 65 cytosolic amino acid residues of rBASIC, only a few are conserved, including the HG motif, which is present in all mammalian Deg/ENaC channels (2). Therefore, we reasoned that the cytosolic N-terminal sequence of rBASIC may contain specific regulatory motifs.…”

Section: Removal Of the Cytosolic N-terminal Region Of Rbasicmentioning

confidence: 99%

“…In humans the degenerin/epithelial Na ϩ channel (Deg/ ENaC) 3 gene family comprises nine genes and in rodents eight genes, which give rise to different subunits of the acid-sensing ion channels (ASICs), to three to four subunits of the epithelial Na ϩ channel, and to the bile acid-sensitive ion channel (BASIC) (1)(2)(3). ASICs are mainly neuronal channels, which are activated by a sudden increase in the extracellular proton concentration (4).…”

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confidence: 99%

“…A large number of studies have shown that the cytosolic domains can either serve as targets for regulatory processes of Deg/ENaC channels or that they can modulate their biophysi-cal properties (2). The epithelial Na ϩ channel (ENaC), for example, contains a conserved PY motif in the C-terminal domain, which serves as binding site for members of the Nedd4 family of ubiquitin ligases (24).…”

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“…Liddle's syndrome, an inherited form of hypertension, is caused by mutations within the Nedd4-binding site of ENaC, which alter ubiquitination and consequently surface expression (24 -26). Several ASICs contain a PDZ motif at their C-terminal domain, which serve as interaction sites for a variety of regulatory proteins (2). ASIC4 was recently shown to traffic predominantly into early endosomes, a process that is mainly controlled by a sequence motif in the N-terminal domain of the channel (27).…”

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A Cytosolic Amphiphilic α-Helix Controls the Activity of the Bile Acid-sensitive Ion Channel (BASIC)

Schmidt

Löhrer

Alsop

et al. 2016

Journal of Biological Chemistry

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Edited by George CarmanThe bile acid-sensitive ion channel (BASIC) is a member of the degenerin/epithelial Na ؉ channel (Deg/ENaC) family of ion channels. It is mainly found in bile duct epithelial cells, the intestinal tract, and the cerebellum and is activated by alterations of its membrane environment. Bile acids, one class of putative physiological activators, exert their effect by changing membrane properties, leading to an opening of the channel. The physiological function of BASIC, however, is unknown. Deg/ ENaC channels are characterized by a trimeric subunit composition. Each subunit is composed of two transmembrane segments, which are linked by a large extracellular domain. The termini of the channels protrude into the cytosol. Many Deg/ ENaC channels contain regulatory domains and sequence motifs within their cytosolic domains. In this study, we show that BASIC contains an amphiphilic ␣-helical structure within its N-terminal domain. This ␣-helix binds to the cytosolic face of the plasma membrane and stabilizes a closed state. Truncation of this domain renders the channel hyperactive. Collectively, we identify a cytoplasmic domain, unique to BASIC, that controls channel activity via membrane interaction.

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Multisensory neural integration of chemical and mechanical signals

Sánchez-Alcañiz

Benton

2017

BioEssays

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Chemosensation and mechanosensation cover an enormous spectrum of processes by which animals use information from the environment to adapt their behavior. For pragmatic reasons, these sensory modalities are commonly investigated independently. Recent advances, however, have revealed numerous situations in which they function together to control animals' actions. Highlighting examples from diverse vertebrates and invertebrates, we first discuss sensory receptors and neurons that have dual roles in the detection of chemical and mechanical stimuli. Next we present cases where peripheral chemosensory and mechanosensory pathways are discrete but intimately packaged to permit coordinated reception of external cues. Finally, we consider how chemical and mechanical signals converge in central neural circuitry to enable multisensory integration. These insights demonstrate how investigation of the interplay between different sensory modalities is key to a more holistic and realistic understanding of sensory-guided behaviors.

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International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na⁺Channel

Cited by 248 publications

References 332 publications

Conformational dynamics and role of the acidic pocket in ASIC pH-dependent gating

Conformational dynamics and role of the acidic pocket in ASIC pH-dependent gating

A Cytosolic Amphiphilic α-Helix Controls the Activity of the Bile Acid-sensitive Ion Channel (BASIC)

Multisensory neural integration of chemical and mechanical signals

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International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na+Channel

Cited by 248 publications

References 332 publications

Conformational dynamics and role of the acidic pocket in ASIC pH-dependent gating

Conformational dynamics and role of the acidic pocket in ASIC pH-dependent gating

A Cytosolic Amphiphilic α-Helix Controls the Activity of the Bile Acid-sensitive Ion Channel (BASIC)

Multisensory neural integration of chemical and mechanical signals

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Product

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International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na⁺Channel