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Background  Neurodevelopment requires thyroid hormone, yet the mechanisms and targets of thyroid hormone action during embryonic stages remain ill-defined. We previously showed that the thyroid hormone thyroxine (T4) rapidly increases voltage-gated sodium current in zebrafish Rohon-Beard cells (RBs), a primary sensory neuron subtype present during embryonic development. Here, we determined essential components of the rapid T4 signaling pathway by identifying the involved intracellular messengers, the targeted sodium channel isotype, and the spatial and temporal expression pattern of the nongenomic αVβ3 integrin T4 receptor.    Results  We first tested which signaling pathways mediate T4's rapid modulation of sodium current (I Na ) by perturbing specific pathways associated with nongenomic thyroid hormone signaling. We found that pharmacological blockade of protein phosphatase 1 and the mitogen-activated protein kinase p38 isoform decreased and increased tonic sodium current amplitudes, respectively, and blockade of either occluded rapid responses to acute T4 application. We next tested for the ion channel target of rapid T4 signaling via morpholino knock-down of specific sodium channel isotypes. We found that selective knock-down of the sodium channel α-subunit Na v 1.6a, but not Na v 1.1la, occluded T4's acute effects. We also determined the spatial and temporal distribution of a nongenomic T4 receptor, integrin αVβ3. At 24 hours post fertilization (hpf), immunofluorescent assays showed no specific integrin αVβ3 immunoreactivity in wild-type zebrafish embryos. However, by 48 hpf, embryos expressed integrin αVβ3 in RBs and primary motoneurons. Consistent with this temporal expression, T4 modulated RB I Na  at 48 but not 24 hpf. We next tested whether T4 rapidly modulated I Na  of caudal primary motoneurons, which express the receptor (αVβ3) and target (Na v 1.6a) of rapid T4 signaling. In response to T4, caudal primary motoneurons rapidly increased sodium current peak amplitude 1.3-fold.    Conclusion  T4's nongenomic regulation of sodium current occurs in different neuronal subtypes, requires the activity of specific phosphorylation pathways, and requires both integrin αVβ3 and Na v 1.6a. Our  in vivo  analyses identify molecules required for T4's rapid regulation of voltage-gated sodium current.

Molecular components underlying nongenomic thyroid hormone signaling in embryonic zebrafish neurons