Rapid signaling at the plasma membrane by a nuclear receptor for thyroid hormone
- Nina M. Storey*,†,
- Saverio Gentile*,
- Hemayet Ullah‡,
- Angela Russo,
- Michelle Muessel,
- Christian Erxleben, and
- David L. Armstrong§
- Membrane Signaling Group, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709
-
Communicated by Lutz Birnbaumer, National Institutes of Health, Research Triangle Park, NC, January 4, 2006
-
↵*N.M.S. and S.G. contributed equally to this work. (received for review December 20, 2005)
Abstract
Many nuclear hormones have physiological effects that are too rapid to be explained by changes in gene expression and are often attributed to unidentified or novel G protein-coupled receptors. Thyroid hormone is essential for normal human brain development, but the molecular mechanisms responsible for its effects remain to be identified. Here, we present direct molecular evidence for potassium channel stimulation in a rat pituitary cell line (GH4C1) by a nuclear receptor for thyroid hormone, TRβ, acting rapidly at the plasma membrane through phosphatidylinositol 3-kinase (PI3K) to slow the deactivation of KCNH2 channels already in the membrane. Signaling was disrupted by heterologous expression of TRβ receptors with mutations in the ligand-binding domain that are associated with neurological disorders in humans, but not by mutations that disrupt DNA binding. More importantly, PI3K-dependent signaling was reconstituted in cell-free patches of membrane from CHO cells by heterologous expression of human KCNH2 channels and TRβ, but not TRα, receptors. TRβ signaling through PI3K provides a molecular explanation for the essential role of thyroid hormone in human brain development and adult lipid metabolism.
Footnotes
- §To whom correspondence should be addressed. E-mail: armstro3{at}niehs.nih.gov
-
↵ †Present address: Department of Cell Physiology and Pharmacology, University of Leicester, Leicester LE1 9HN, United Kingdom.
-
↵ ‡Present address: Department of Biology, Howard University, Washington, DC 20059.
-
Author contributions: N.M.S., S.G., H.U., C.E., and D.L.A. designed research; N.M.S., S.G., H.U., A.R., M.M., and C.E. performed research; N.M.S., S.G., H.U., A.R., M.M., C.E., and D.L.A. analyzed data; and D.L.A. wrote the paper.
-
Conflict of interest statement: No conflicts declared.
- Abbreviations:
- PI3K,
- phosphatidylinositol 3-kinase;
- PIP3,
- phosphatidylinositol 3,4,5-trisphosphate;
- T3,
- l-3,5,3′-triiodothyronine.
