In this thesis, it has been discovered that thyroid hormones, particularly T3, can activate or modulate acid-sensing ion channels (ASICs) in a subtype-specific manner. For rat ASICs (rASICs), T3 enhanced the amplitude of rASIC1a and rASIC3 currents, but with different mechanisms. For rASIC1a, T3 increased proton efficacy without altering proton sensitivity. This was supported by the observation that T3 potentiated rASIC1a currents both at pH 6.5 (near its pH50) and at pH 6.0 (when the channel is fully activated). In contrast, T3 increased the proton affinity of rASIC3 without affecting its proton efficacy. This was evident from a leftward shift in both the activation and steady-state desensitization (SSD) curves. Since the activation curve shifted more strongly than the SSD curve, the overlap between them, corresponding to the window current, was enlarged. For human ASICs (hASICs), T3 exhibited subtype-specific effects as well. Similar to rASICs, T3 also potentiated hASIC1a transient currents. However, in the case of homomeric hASIC3, T3 directly activated the channel at neutral or even alkaline pH, inducing a sustained inward current. This T3-induced current was sensitive to amiloride, a classical ASIC blocker, and had a positive reversal potential, suggesting it was carried primarily by Na+ ions. Interestingly, T3 did not modulate or activate the heteromeric hASIC1a/3 channel. These findings were observed with recombinant ASICs expressed either in Xenopus oocytes or in human embryonic kidney (HEK) cells. Endogenous ASIC currents in the human thyroid epithelial cell line Nthy-ori-3-1 were not potentiated by T3, suggesting that heteromeric ASIC1/3 channels predominate in these cells. In addition to ASIC-related effects, an outward current was observed in Nthy-ori 3-1 cells when T3 was applied at low extracellular pH. This current was mediated by Ca2+-activated potassium channels, which were activated in response to increased intracellular Ca2+ concentrations. Since both the outward current and Ca2+ signaling were abolished by YM-254890, a broad-spectrum inhibitor of G protein-coupled receptor (GPCR) pathways, it is likely that this response was initiated via activation of an unidentified GPCR.
Lu Qin (Thu,) studied this question.