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J. Biol. Chem., Vol. 281, Issue 2, 714-722, January 13, 2006

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Trypsin Cleaves Acid-sensing Ion Channel 1a in a Domain That Is Critical for Channel Gating^*

From the Département de Pharmacologie et de Toxicologie, Université de Lausanne, Switzerland

Acid-sensing ion channels (ASICs) are neuronal Na⁺ channels that are members of the epithelial Na⁺ channel/degenerin family and are transiently activated by extracellular acidification. ASICs in the central nervous system have a modulatory role in synaptic transmission and are involved in cell injury induced by acidosis. We have recently demonstrated that ASIC function is regulated by serine proteases. We provide here evidence that this regulation of ASIC function is tightly linked to channel cleavage. Trypsin cleaves ASIC1a with a similar time course as it changes ASIC1a function, whereas ASIC1b, whose function is not modified by trypsin, is not cleaved. Trypsin cleaves ASIC1a at Arg-145, in the N-terminal part of the extracellular loop, between a highly conserved sequence and a sequence that is critical for ASIC1a inhibition by the venom of the tarantula Psalmopoeus cambridgei. This channel domain controls the inactivation kinetics and co-determines the pH dependence of ASIC gating. It undergoes a conformational change during inactivation, which renders the cleavage site inaccessible to trypsin in inactivated channels.

Received for publication, September 23, 2005 , and in revised form, November 4, 2005.

^* This work was supported by the Swiss National Science Foundation (Grant 3100A0-105262/1 to S. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 4121-692-5422; Fax: 4121-692-5355; E-mail: Stephan.Kellenberger{at}unil.ch.

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