Sensory neuron sodium current requires nongenomic actions of thyroid hormone during development.
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 alphaVbeta3, 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.
Yonkers
Marc A
MA
Department of Physiology and Biophysics, University of Colorado Denver at AMC, RC-1 North Tower, Room 7403A, PO Box 6511, Mail Stop F8307, Aurora, CO 80045, USA. marc.yonkers@uchsc.edu
Ribera
Angeles B
AB
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004625:Embryo, Nonmammalian; D066298:In Vitro Techniques; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors; D008954:Models, Biological; D018408:Patch-Clamp Techniques; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000528:radiation effects; D015222:Sodium Channels / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology; D013963:Thyroid Hormones / Q000378:metabolism / Q000494:pharmacology*; D013974:Thyroxine / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D014110:Touch; D015027:Zebrafish
D000911:Antibodies, Monoclonal; D039302:Integrin alphaVbeta3; D015222:Sodium Channels; D013963:Thyroid Hormones; C011126:tetraiodothyroacetic acid; D013974:Thyroxine
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