title: Sensory neuron sodium current requires nongenomic actions of thyroid hormone during development.
abstract: 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.
authors.affiliation: 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
authors.forename: Marc A
authors.initials: MA
authors.lastname: Yonkers
authors.forename: Angeles B
authors.initials: AB
authors.lastname: Ribera
mesh_terms: 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
chemical_list: D000911:Antibodies, Monoclonal; D039302:Integrin alphaVbeta3; D015222:Sodium Channels; D013963:Thyroid Hormones; C011126:tetraiodothyroacetic acid; D013974:Thyroxine
references.citation: Best Pract Res Clin Endocrinol Metab. 2007 Jun;21(2):253-64
references.pmid: 17574007
references.citation: J Clin Endocrinol Metab. 2002 Apr;87(4):1768-77
references.pmid: 11932315
references.citation: J Cell Physiol. 2006 Apr;207(1):220-31
references.pmid: 16331687
references.citation: Circ Res. 2004 Jun 11;94(11):1500-6
references.pmid: 15117822
references.citation: JAMA. 2004 Aug 11;292(6):691-5
references.pmid: 15304465
references.citation: Gen Comp Endocrinol. 2007 Jun-Jul;152(2-3):206-14
references.pmid: 17418841
references.citation: Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13011-6
references.pmid: 9371791
references.citation: Neuroscience. 2006;137(1):125-32
references.pmid: 16289831
references.citation: J Neurophysiol. 2005 Jun;93(6):3582-93
references.pmid: 15673553
references.citation: J Pediatr Endocrinol Metab. 2000 Feb;13(2):191-4
references.pmid: 10711665
references.citation: N Engl J Med. 1989 Jul 6;321(1):13-6
references.pmid: 2733742
references.citation: J Neurosci. 1998 Nov 15;18(22):9181-91
references.pmid: 9801358
references.citation: J Physiol. 2003 Jan 15;546(Pt 2):491-9
references.pmid: 12527735
references.citation: Thyroid. 1996 Oct;6(5):497-504
references.pmid: 8936679
references.citation: J Pediatr. 1995 Aug;127(2):275-7
references.pmid: 7636655
references.citation: Mol Cell Neurosci. 2003 May;23(1):54-68
references.pmid: 12799137
references.citation: J Physiol. 1984 Sep;354:345-62
references.pmid: 6481637
references.citation: J Clin Endocrinol Metab. 1993 Dec;77(6):1719-22
references.pmid: 8263162
references.citation: Trends Endocrinol Metab. 2005 Nov;16(9):429-35
references.pmid: 16214361
references.citation: J Int Neuropsychol Soc. 2001 Sep;7(6):734-44
references.pmid: 11575595
references.citation: Brain Res. 1990 May 28;517(1-2):88-98
references.pmid: 2376010
references.citation: Fish Physiol Biochem. 1990 Nov;8(6):515-20
references.pmid: 24221039
references.citation: J Physiol. 1984 Mar;348:511-25
references.pmid: 6201612
references.citation: Dev Dyn. 1995 Jul;203(3):253-310
references.pmid: 8589427
references.citation: J Biol Chem. 1987 Dec 25;262(36):17703-11
references.pmid: 2447074
references.citation: Endocrinology. 2006 Apr;147(4):1602-7
references.pmid: 16384862
references.citation: J Mol Cell Cardiol. 1999 Apr;31(4):881-93
references.pmid: 10329215
references.citation: Acta Paediatr. 2000 Mar;89(3):291-5
references.pmid: 10772276
references.citation: Development. 2006 Oct;133(19):3827-36
references.pmid: 16943272
references.citation: Development. 2001 Sep;128(18):3511-20
references.pmid: 11566856
references.citation: Proc Biol Sci. 1997 Mar 22;264(1380):367-73
references.pmid: 9107052
references.citation: J Nutr. 2000 Feb;130(2S Suppl):493S-495S
references.pmid: 10721937
references.citation: Am J Dis Child. 1987 Oct;141(10):1081-3
references.pmid: 3630993
references.citation: Eur J Obstet Gynecol Reprod Biol. 1994 May 18;54(3):159-63
references.pmid: 7523202
references.citation: Development. 1996 Dec;123:399-413
references.pmid: 9007258
references.citation: Endocrinology. 2005 Jul;146(7):2864-71
references.pmid: 15802494
references.citation: J Clin Endocrinol Metab. 1988 Oct;67(4):853-6
references.pmid: 3417852