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This Podcast features an interview with Renate Pilz, senior author of a Research Article that appears in the 20 May 2014 issue of Science Signaling, about how thyroid hormone triggers signaling at the plasma membrane. Thyroid is best known as a ligand for nuclear hormone receptors, which are transcription factors that mediate activation or repression of target genes ligand-dependently. This genomic response to thyroid hormone results in changes in gene expression that, in turn, affect cell biology and metabolism. However, thyroid hormone also elicits rapid, transcription-independent cellular responses by initiating intracellular signaling pathways. Kalyanaraman et al. identified an alternative, membrane-associated form of a nuclear thyroid hormone receptor that mediates nongenomic thyroid hormone signaling in osteoblasts.