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 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.
Department of Otolaryngology, Research Group of Sensory Physiology, D-72076 Tübingen, Germany.
Elena
E
Babini
Martin
M
Paukert
Hyun-Soon
HS
Geisler
Stefan
S
Grunder
D062565:Acid Sensing Ion Channels; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins; D009865:Oocytes; D020033:Protein Isoforms; D015222:Sodium Channels / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D013096:Spermine / Q000494:pharmacology; D014982:Xenopus laevis
C568266:ASIC1 protein, human; C112231:ASIC3 protein, human; D062565:Acid Sensing Ion Channels; D007473:Ion Channels; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D015222:Sodium Channels; D013096:Spermine; D002118:Calcium