(The FASEB Journal. 2008;22:937.26)
© 2008 FASEB
(The FASEB Journal. 2008;22:937.26.)
© 2008 FASEB
ASIC Channels Inhibit BK Potassium Channels by a Toxin-Like Extracellular Motif
Elena Petroff1,
Margaret P Price1,
Vladislav Snitsarev1,
Huiyu Gong1,
Francois M Abboud1 and
Michael J Welsh1,2
1 Internal Medicine, University of Iowa, Iowa City, IA
2 HHMI, Iowa City, IA
ABSTRACT
Acid-sensing ion channels (ASICs) contain a large extracellular domain whose function has remained largely unknown. Within this domain sits a highly conserved sequence which resembles the scorpion toxin sequence that binds and inhibits large conductance calcium-activated potassium channel (BK). We hypothesized that ASICs might interact with and inhibit BK. In transfected HEK 293 cells, we found that ASIC1a inhibited BK currents. Lowering extracellular pH relieved the inhibition.
ASIC2a, –2b and –3 also inhibited BK currents, and the pH-dependent relief of inhibition varied between ASIC channels. In scorpion toxins, the cationic residues in the RGKC/RFGKC sequence are critical for inhibition. When we mutated the equivalent R and K residues in ASICs to A or E, the inhibition of BK channels was abolished. To test for an interaction of the endogenous proteins, we studied cultured cortical neurons and found an ASIC-dependent inhibition of BK current and its pH-dependent relief. BK currents were larger in ASIC1a/2/3 knockout mice, consistent with the lack of inhibition. In addition, the two proteins co-precipitated from transfected cells and whole brain. These data indicate that a toxin-like sequence in the extracellular domain of ASICs inhibits BK channels. This novel mechanism for regulating potassium channel activity may influence neuronal excitability. Support: HL014388 to FMA.
