Rapid signaling at the plasma membrane by a nuclear receptor for thyroid hormone.
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 (GH(4)C(1)) by a nuclear receptor for thyroid hormone, TRbeta, 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 TRbeta 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 TRbeta, but not TRalpha, receptors. TRbeta signaling through PI3K provides a molecular explanation for the essential role of thyroid hormone in human brain development and adult lipid metabolism.
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, USA.
Nina M
NM
Storey
Saverio
S
Gentile
Hemayet
H
Ullah
Angela
A
Russo
Michelle
M
Muessel
Christian
C
Erxleben
David L
DL
Armstrong
D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D006224:Cricetinae; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating; D018408:Patch-Clamp Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014284:Triiodothyronine / Q000378:metabolism* / Q000494:pharmacology
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C000606918:Kcnh2 protein, rat; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; D019869:Phosphatidylinositol 3-Kinases