The rapid effects of thyroid hormone on the activity of Kv11.1 channels in rat pituitary cells were recently shown (Storey et al 2006) to be mediated by the classical nuclear receptor for thyroid hormone, TRβ, acting at the plasma membrane through the phosphoinositide 3 kinase (PI3K) and the Rac GTPase, which is a well-known effector of PIP3 dependent Rac exchange factors. Thus, Kv11.1 channel stimulation by thyroid hormone was blocked by inhibiting PI3K with wortmannin or dominant negative Rac 17N and restored by exogenous application of 3,4,5-PIP3, the immediate product of PI3K action, or by constitutively active Rac 61L. More importantly signaling was reconstituted in CHO cells by heterologous expression of human Kv11.1 channels and the human TRβ but not the TRα receptor. We have continued to investigate the mechanism of PI3K stimulation by TRβ and the consequences of PI3K signaling for the physiological effects of thyroid hormone. We have used immunoprecipitation to show that TRβ associates with the regulatory p85 subunit of PI3K in the absence of ligand, but dissociates in the presence of thyroid hormone. We have also observed rapid thyroid hormone-dependent phosphorylation of the Akt protein kinase and recruitment of Rac to the plasma membrane confirming that thyroid hormone stimulates PI3K-dependent effectors. Other proteins interact with p85 through two Src homology (SH2) domains which recognize phosphotyrosine. TRβ but not TRα contains a consensus SH2-binding domain with high affinity for p85. Mutating the tyrosine in that consensus site to phenylalanine prevents reconstitution of Kv11.1 regulation by thyroid hormone in CHO cells.
| Hönes, G Sebastian; Rakov, Helena; Logan, John et al. (2017) Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo. Proc Natl Acad Sci U S A 114:E11323-E11332 |
| Martin, Negin P; Marron Fernandez de Velasco, Ezequiel; Mizuno, Fengxia et al. (2014) A rapid cytoplasmic mechanism for PI3 kinase regulation by the nuclear thyroid hormone receptor, TR?, and genetic evidence for its role in the maturation of mouse hippocampal synapses in vivo. Endocrinology 155:3713-24 |
| Storey, Nina M; Gentile, Saverio; Ullah, Hemayet et al. (2006) Rapid signaling at the plasma membrane by a nuclear receptor for thyroid hormone. Proc Natl Acad Sci U S A 103:5197-201 |
