Regulation Of The Acetylcholine Receptor Function By Thyroid Hormones

The basic molecular mechanisms underlying the muscular weakness initiated early during thyroid dysfunction are poorly understood. In this work we have explored how the acute and chronic alterations of thyroid hormones (THs) affect the acetylcholine receptor (AChR) channel function in the neuromuscular junction (NMJ). Acute methimazole (MMI) treatment produced a significant (p<0.005) reduction in weight of euthyroid mice of 8.64%, induced by a transient hyperthyroid phase. This result is compatible with the loss of weight produced acutely by T3 (1μg/g-bw) of 4.11%. The resulting action of these acute treatments is a significantly (p<0.001) reduced muscular strength by MMI (58.0%) and T3 (52.9%) when compared to sham animals. The hypothyroidism induced by the chronic MMI treatment causes a reduced daily weight gain of 76.5%. Focal recordings of miniature endplate currents (MEPCs) in isolated NMJ of chronically MMI-treated mice revealed a significant (p<0.001) reduction in the frequency (57.7%), amplitude (59.3%), and decay time (66.7%). The electrophysiological results appear to be related to the membrane-lipid metabolism in particular cholesterol, since NMJ of hypothyroid mice treated with methyl-beta-cyclodextrin (MβCD) recover the MEPCs normal characteristics. This data also agrees with results where the MEPCs’ decay time 1.45 ± 0.06 ms (n=8) of fat euthyroid mice differs significantly (p<0.001) from those of slim animals 1.01 ± 0.08 ms (n=7). The relationship between weight (w) and decay time (τ) is well-described by the equation: τ = -0.00447w + 2.456. We propose that membrane cholesterol in the NMJ could be an important target for the in vivo regulation of synaptic activity during thyroid dysfunction. Importantly, the docking of cholesterol to the AChR occurs in the C418 vicinity, a highly relevant residue in the protein-lipid interface.NIH 5S06 GM050595 and G12 RR03035 to LVR