title: Insight toward epithelial Na+ channel mechanism revealed by the acid-sensing ion channel 1 structure.
abstract: The epithelial Na(+) channel/degenerin (ENaC/DEG) protein family includes a diverse group of ion channels, including nonvoltage-gated Na(+) channels of epithelia and neurons, and the acid-sensing ion channel 1 (ASIC1). In mammalian epithelia, ENaC helps regulate Na(+) and associated water transport, making it a critical determinant of systemic blood pressure and pulmonary mucosal fluidity. In the nervous system, ENaC/DEG proteins are related to sensory transduction. While the importance and physiological function of these ion channels are established, less is known about their structure. One hallmark of the ENaC/DEG channel family is that each channel subunit has only two transmembrane domains connected by an exceedingly large extracellular loop. This subunit structure was recently confirmed when Jasti and colleagues determined the crystal structure of chicken ASIC1, a neuronal acid-sensing ENaC/DEG channel. By mapping ENaC to the structural coordinates of cASIC1, as we do here, we hope to provide insight toward ENaC structure. ENaC, like ASIC1, appears to be a trimeric channel containing 1alpha, 1beta, and 1gamma subunit. Heterotrimeric ENaC and monomeric ENaC subunits within the trimer possibly contain many of the major secondary, tertiary, and quaternary features identified in cASIC1 with a few subtle but critical differences. These differences are expected to have profound effects on channel behavior. In particular, they may contribute to ENaC insensitivity to acid and to its constitutive activity in the absence of time- and ligand-dependent inactivation. Experiments resulting from this comparison of cASIC1 and ENaC may help clarify unresolved issues related to ENaC architecture, and may help identify secondary structures and residues critical to ENaC function.
authors.affiliation: Department of Physiology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA. stockand@uthscsa.edu
authors.forename: James D
authors.initials: JD
authors.lastname: Stockand
authors.forename: Alexander
authors.initials: A
authors.lastname: Staruschenko
authors.forename: Oleh
authors.initials: O
authors.lastname: Pochynyuk
authors.forename: Rachell E
authors.initials: RE
authors.lastname: Booth
authors.forename: Dee U
authors.initials: DU
authors.lastname: Silverthorn
mesh_terms: D062565:Acid Sensing Ion Channels; D000595:Amino Acid Sequence; D000818:Animals; D053503:Epithelial Sodium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: C568266:ASIC1 protein, human; D062565:Acid Sensing Ion Channels; D053503:Epithelial Sodium Channels; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; D015222:Sodium Channels; D012964:Sodium