them to bind isomers of retinoic acid with similar affinities. Once RXRs bind ligand, they undergo conformational changes that reduce their affinity for corepressors—allowing them to attract coactivators to the transcription site. Once all of the necessary cofactors are present, the presence of a DNA binding domain permits the binding of response elements, initiating gene transcription. Due to their role in gene regulation, studies have shown that these receptors are necessary for growth and development. Regulation of TRE gene products In the absence of hormone, TR forms a complex with corepressor proteins such as nuclear receptor co-repressor 1 (N-CoR) and 2 (N-CoR2). While these cofactors are present, TR binds HREs in a transcriptionally inactive state. This inhibition of gene transcription allows for tight regulation of gene products. Binding of thyroid hormone results in a conformational change in helix 12 of the TR transactivation domain, which displaces the corepressors from the receptor/DNA complex. Coactivator proteins are recruited, forming a DNA/TR/coactivator complex. One coactivator recruited to the site is nuclear receptor co-activator 1 (NCoA-1). RNA polymerase is recruited to the site and transcribes downstream DNA into messenger RNA (mRNA). The mRNA generated is then translated into the corresponding proteins. The protein products from this process drive the changes in cell function observed in the presence of thyroid hormone. Non-genomic signaling pathway Non-genomic effects are faster than genomic effects because they do not require transcription and translation—two very precise and time-consuming processes. Initially most scientists presumed that non-genomic effects were mediated by non-nuclear receptors, but now there is growing evidence for non-genomic effects mediated in the cytoplasm by the traditional nuclear receptors. For example, TR-α1 (a specific isoform of TR) has been linked to cell viability, which is hypothesized to involve a rise in cGMP concentration (through an unknown mechanism) and the corresponding activation of protein kinase G. Other non-genomic effects that have been observed include the regulation of mitochondrial metabolism, stimulation of glucose uptake, altering cytoskeleton organization, regulating ion pump concentrations at the membrane, and the regulation of osteogenesis. Unfortunately, no specific molecular mechanisms have been provided for these nongenomic signaling pathways, so testing the relative importance of genomic and nongenomic signaling by the nuclear receptors using specific mutations that selectively eliminate one action or the other was not carried out. In contrast, more recently, a specific molecular mechanism for TR-β signaling through the PI3 kinase has been identified, which allowed scientists