title: Selective regulation of acid-sensing ion channel 1 by serine proteases.
abstract: Acid-sensing ion channels (ASICs) are neuronal Na(+) channels that belong to the epithelial Na(+) channel/degenerin family. ASICs are transiently activated by a rapid drop in extracellular pH. Conditions of low extracellular pH, such as ischemia and inflammation in which ASICs are thought to be active, are accompanied by increased protease activity. We show here that serine proteases modulate the function of ASIC1a and ASIC1b but not of ASIC2a and ASIC3. We show that protease exposure shifts the pH dependence of ASIC1a activation and steady-state inactivation to more acidic pH. As a consequence, protease exposure leads to a decrease in current response if ASIC1a is activated by a pH drop from pH 7.4. If, however, acidification occurs from a basal pH of approximately 7, protease-exposed ASIC1a shows higher activity than untreated ASIC1a. We provide evidence that this bi-directional regulation of ASIC1a function also occurs in neurons. Thus, we have identified a mechanism that modulates ASIC function and may allow ASIC1a to adapt its gating to situations of persistent extracellular acidification.
authors.affiliation: Département de Pharmacologie et de Toxicologie, Université de Lausanne, Rue du Bugnon 27, CH-1005 Lausanne, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Poirot
authors.forename: Marija
authors.initials: M
authors.lastname: Vukicevic
authors.forename: Anne
authors.initials: A
authors.lastname: Boesch
authors.forename: Stephan
authors.initials: S
authors.lastname: Kellenberger
mesh_terms: D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D006224:Cricetinae; D062626:Degenerin Sodium Channels; D004594:Electrophysiology; D053503:Epithelial Sodium Channels; D006624:Hippocampus / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007249:Inflammation; D007473:Ion Channels / Q000378:metabolism*; D007477:Ions; D007700:Kinetics; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014357:Trypsin / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D062626:Degenerin Sodium Channels; D053503:Epithelial Sodium Channels; D007473:Ion Channels; D007477:Ions; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D012697:Serine Endopeptidases; D014357:Trypsin