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Sensory Neuron Sodium Current Requires Nongenomic Actions of Thyroid Hormone During Development

Department of Physiology and Biophysics, Medical Scientist Training Program, Neuroscience Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado

Submitted 24 July 2008; accepted in final form 11 September 2008

Development of the embryonic nervous system requires thyroid hormone. However, the underlying mechanisms and targets of thyroid hormone action are not well defined. To identify embryonic roles for thyroid hormone we tested for effects on a key neuronal trait, voltage-gated sodium current (I_Na), in the zebrafish model system. We recorded from Rohon–Beard sensory neurons (RBs) using whole cell voltage-clamp methods. Here, we provide in vivo evidence for thyroid hormone regulation of I_Na. Chronic thyroid hormone application increased RB peak I_Na density 1.4-fold. However, I_Na density showed a similar increase within 5 min of an acute hormone application, a time course not expected for a genomic mechanism. Tetraiodothyroacetic acid (tetrac), a thyroid hormone blocker, blocked both chronic and acute effects. Further, the thyroid hormone precursor thyroxine (T4) affected I_Na, yet the traditionally active form triiodothyronine did not. Consequently, we tested for a nonconventional T4 receptor. LM609, a selective antagonist of integrin Vβ3, occluded the rapid effect of T4, implicating a specific integrin dimer as a T4 receptor. Chronic application of either tetrac or LM609 significantly reduced sodium conductance, demonstrating an in vivo requirement for T4-integrin regulation of I_Na. Further, removing endogenous T4 levels via yolkectomy reduced sodium conductance, an effect that was partially rescued by T4 supplementation following surgery. Because RBs mediate the embryonic touch response, we tested for behavioral effects. Tetrac and LM609 significantly reduced the percentage of touch trials eliciting a normal touch response. T4's rapid effect on RB I_Na highlights the importance of embryonic T4 availability and nongenomic T4 signaling.

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