Thyroid hormones are positive allosteric modulators of acid-sensing ion channels ASIC1a and ASIC3

Acid-sensing ion channels (ASICs) are excitatory ligand-gated ion channels directly gated by extracellular protons. Proton-sensitivity of ASICs is subject to modulation by different compounds, for example neuropeptides and lipids. In this study, we uncovered that the currents of the two most proton-sensitive ASICs, homomeric ASIC1a and ASIC3, are strongly potentiated by thyroid hormones, particularly triiodothyronine (T3). Potentiation by T3 had micromolar affinities and rapid on- and offset kinetics. Moreover, T3 did not affect gramicidin A-induced currents, suggesting that thyroid hormones had direct action on ASICs, indicating that they are a new class of allosteric ASIC modulators. Interestingly, for ASIC1a, T3 increased the efficacy of protons, whereas for ASIC3, it increased potency of protons. These results suggest that thyroid hormones could modulate ASIC activity in particular brain regions where their concentration is sufficiently high.