Alternative Splicing and Interaction with Di- and Polyvalent Cations Control the Dynamic Range of Acid-sensing Ion Channel 1 (ASIC1)

Homomeric acid-sensing ion channel 1 (ASIC1) can be activated by extracellular H + in the physiological pH range and may, therefore, contribute to neurotransmission and peripheral pain perception. ASIC1a and ASIC1b are alternative splice products of the ASIC1 gene. Here we show that both splice vari...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-11, Vol.277 (44), p.41597-41603
Main Authors: Babini, Elena, Paukert, Martin, Geisler, Hyun-Soon, Grunder, Stefan
Format: Article
Language:English
Subjects:
Acid Sensing Ion Channels
Alternative Splicing
Amino Acid Sequence
Animals
Binding Sites
Calcium - pharmacology
Hydrogen-Ion Concentration
Ion Channels - drug effects
Ion Channels - physiology
Membrane Proteins
Molecular Sequence Data
Nerve Tissue Proteins
Oocytes
Protein Isoforms
Sodium Channels - chemistry
Sodium Channels - drug effects
Sodium Channels - physiology
Spermine - pharmacology
Xenopus laevis
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Summary:Homomeric acid-sensing ion channel 1 (ASIC1) can be activated by extracellular H + in the physiological pH range and may, therefore, contribute to neurotransmission and peripheral pain perception. ASIC1a and ASIC1b are alternative splice products of the ASIC1 gene. Here we show that both splice variants show steady-state inactivation when exposed to slightly decreased pH, limiting their operational range. Compared with ASIC1a, steady-state inactivation and pH activation of ASIC1b are shifted to more acidic values by 0.25 and 0.7 pH units, respectively, extending the dynamic range of ASIC1. Shifts of inactivation and activation are intimately linked; only two amino acids in the ectodomain, which are exchanged by alternative splicing, control both properties. Moreover, we show that extracellular, divalent cations like Ca 2+ and Mg 2+ as well as the polyvalent cation spermine shift the steady-state inactivation of ASIC1a and ASIC1b to more acidic values. This leads to a potentiation of the channel response and is due to a stabilization of the resting state. Our results indicate that ASIC1b is an effective sensor of transient H + signals during slight acidosis and that, in addition to alternative splicing, interaction with di- and polyvalent cations extends the dynamic range of ASIC H + sensors.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M205877200