PT  - JOURNAL ARTICLE
AU  - Thomas W. Sherwood
AU  - Kirsten G. Lee
AU  - Matthew G. Gormley
AU  - Candice C. Askwith
TI  - Heteromeric Acid-Sensing Ion Channels (ASICs) Composed of ASIC2b and ASIC1a Display Novel Channel Properties and Contribute to Acidosis-Induced Neuronal Death
AID  - 10.1523/JNEUROSCI.1665-11.2011
DP  - 2011 Jun 29
TA  - The Journal of Neuroscience
PG  - 9723--9734
VI  - 31
IP  - 26
4099  - http://www.jneurosci.org/content/31/26/9723.short
4100  - http://www.jneurosci.org/content/31/26/9723.full
SO  - J. Neurosci.2011 Jun 29; 31
AB  - Acid-sensing ion channel (ASIC) subunits associate to form homomeric or heteromeric proton-gated ion channels in neurons throughout the nervous system. The ASIC1a subunit plays an important role in establishing the kinetics of proton-gated currents in the CNS, and activation of ASIC1a homomeric channels induces neuronal death after local acidosis that accompanies cerebral ischemia. The ASIC2b subunit is expressed in the brain in a pattern that overlaps ASIC1a, yet the contribution of ASIC2b has remained elusive. We find that coexpression of ASIC2b with ASIC1a in Xenopus oocytes results in novel proton-gated currents with properties distinct from ASIC1a homomeric channels. In particular, ASIC2b/1a heteromeric channels are inhibited by the nonselective potassium channel blockers tetraethylammonium and barium. In addition, steady-state desensitization is induced at more basic pH values, and Big Dynorphin sensitivity is enhanced in these unique heteromeric channels. Cultured hippocampal neurons show proton-gated currents consistent with ASIC2b contribution, and these currents are lacking in neurons from mice with an ACCN1 (ASIC2) gene disruption. Finally, we find that these ASIC2b/1a heteromeric channels contribute to acidosis-induced neuronal death. Together, our results show that ASIC2b confers unique properties to heteromeric channels in central neurons. Furthermore, these data indicate that ASIC2, like ASIC1, plays a role in acidosis-induced neuronal death and implicate the ASIC2b/1a subtype as a novel pharmacological target to prevent neuronal injury after stroke.