Candidate amino acids involved in H+ gating of acid-sensing ion channel 1a.
Acid-sensing ion channels are ligand-gated cation channels, gated by extracellular H(+). H(+) is the simplest ligand possible, and whereas for larger ligands that gate ion channels complex binding sites in the three-dimensional structure of the proteins have to be assumed, H(+) could in principle gate a channel by titration of a single amino acid. Experimental evidence suggests a more complex situation, however. For example, it has been shown that extracellular Ca(2+) ions compete with H(+); probably Ca(2+) ions bound to the extracellular loop of ASICs stabilize the closed state of the channel and have to be displaced before the channel can open. In such a scheme, amino acids contributing to Ca(2+) binding would also be candidates contributing to H(+) gating. In this study we systematically screened more than 40 conserved, charged amino acids in the extracellular region of ASIC1a for a possible contribution to H(+) gating. We identified four amino acids where substitution strongly affects H(+) gating: Glu(63), His(72)/His(73), and Asp(78). These amino acids are highly conserved among H(+)-sensitive ASICs and are candidates for the "H(+) sensor" of ASICs.
Paukert
Martin
M
Department of Physiology II, University of Tübingen, Gmelinstrasse 5, 72076 Tübingen, Germany. Electronic address: mpauker1@jhmi.edu.
Chen
Xuanmao
X
Department of Physiology II, University of Tübingen, Gmelinstrasse 5, 72076 Tübingen, Germany; Department of Physiology II, University of Würzburg, Röntgenring 9, 97070 Würzburg, Germany.
Polleichtner
Georg
G
Department of Physiology II, University of Würzburg, Röntgenring 9, 97070 Würzburg, Germany.
Schindelin
Hermann
H
Rudolf Virchow Center for Experimental Biomedicine and Institute of Structural Biology, University of Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany.
Gründer
Stefan
S
Department of Physiology II, University of Tübingen, Gmelinstrasse 5, 72076 Tübingen, Germany; Department of Physiology II, University of Würzburg, Röntgenring 9, 97070 Würzburg, Germany. Electronic address: stefan.gruender@uni-wuerzburg.de.
D062565:Acid Sensing Ion Channels; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000596:Amino Acids / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D006639:Histidine / Q000235:genetics / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating / Q000235:genetics* / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D009865:Oocytes / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D017386:Sequence Homology, Amino Acid; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D062565:Acid Sensing Ion Channels; D000596:Amino Acids; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D015222:Sodium Channels; D001224:Aspartic Acid; D018698:Glutamic Acid; D006639:Histidine; D002118:Calcium