Rho stimulation by G(13)-coupled receptors and Rac stimulation by nuclear hormones through PI3-kinase may be general mechanisms for regulating ion channel activity in many cell types. Disruption of these novel signaling cascades is predicted to contribute to several specific human neurological diseases, including epilepsy and deafness.

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 4C1) by a nuclear receptor for thyroid hormone, TR␤, 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 TR␤ 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 TR␤, but not TR␣, receptors. TR␤ signaling through PI3K provides a molecular explanation for the essential role of thyroid hormone in human brain development and adult lipid metabolism.neuronal development ͉ phosphatidylinositol 3-kinase ͉ potassium channels ͉ Rac ͉ KCNH2 T he thyroid hormone, L-3,5,3Јtriiodothyronine (T 3 ), plays an essential role in the development and metabolism of many tissues and organs (1). In particular, mammalian brain development is disrupted when T 3 signaling is reduced by inherited mutations in the T 3 receptor gene, THR␤, or when the synthesis or transport of the T 3 prohormone thyroxine (tetraiodothyronine) is reduced by dietary iodine deficiency or environmental toxicants (2-4). T 3 also regulates its own circulating levels through negative feedback on pituitary thyrotropes, which secrete thyroid stimulating hormone (1). Two genes, THR␣ and THR␤, encode four alternately spliced ligand-binding zincfinger receptor proteins from the c-erbA family, which mediate T 3 actions on gene expression (5), but specific T 3 -regulated genes involved directly in neural development remain to be identified. Recently, however, attention has shifted to the rapid, nongenomic signaling by T 3 (6) and other thyroxine metabolites (7).For example, we previously reported a Rac-dependent effect of T 3 on voltage-activated potassium channels encoded by the ether-a-go-go-related gene KCNH2 in a rat pituitary cell line (8). KCNH2 proteins are voltage-activated potassium channels that regulate spike frequency in electrically excitable cells, such as the endocrine cells of the pituitary, through their unique kinetics of inactivation and recovery (9). Because they inactivate almost immediately after activation at positive voltages during the peak of each spike, and then reactivate before closing when the membrane repolarizes after the spike, they contribute to determining the interspike interval. Thus, increasing KCNH2 activity decreases excitability and secretion. Rapid effects of thyroid hormo...

The loss of intracellular potassium is a pivotal step in the induction of apoptosis but the mechanisms underlying this response are poorly understood. Here we report caspase-dependent stimulation of potassium channels by the Fas receptor in a human Jurkat T cell line. Receptor activation with Fas ligand for 30 min increased the amplitude of voltage-activated potassium currents 2-fold on average. This produces a sustained outward current, ϳ10 pA, at physiological membrane potentials during Fas ligand-induced apoptosis. Both basal and Fas ligand-induced currents were blocked completely by toxins that selectively inhibit Kv1.3 potassium channels. Kv1.3 stimulation required the expression of Fasassociated death domain protein and activation of caspase 8, but did not require activation of caspase 3 or protein synthesis. Furthermore, Kv1.3 stimulation by Fas ligand was prevented by chronic stimulation of protein kinase C with 20 nM phorbol 12-myristate 13-acetate during Fas ligand treatment, which also blocks apoptosis. Thus, Fas ligand increases Kv1.3 channel activity through the same canonical apoptotic signaling cascade that is required for potassium efflux, cell shrinkage, and apoptosis.