Intracellular Receptors in Signal Transduction and Second Messengers

Intracellular receptors require ligands that are membrane permeable and include receptors for steroid hormones, lipophilic vitamins, and small molecules such as nitric oxide and hydrogen peroxide. Members of the steroid hormone receptor family are structurally similar and exhibit similarities in their molecular mechanisms. In the absence of ligand, the receptor is retained in the cytoplasm by binding to heat shock protein 90 (HSP90), which conceals the receptor's nuclear localization signal. Following ligand binding, HSP90 is released and the receptor rapidly translocates to the nucleus. Steroid receptors function as transcription factors, thus once in the nucleus they bind to specific steroid response elements on the DNA. These sequences are found in the regulatory region of genes, and binding by steroid receptors can either increase or decrease transcriptional activity of the gene. For example, glucocorticoids promote nuclear import of the glucocorticoid receptor, which results in an upregulation of anti-inflammatory genes and a downregulation of pro-inflammatory cytokines. Changes in gene transcription mediated by steroid receptors are relatively slow in onset yet result in long-term changes in gene expression. Thus pharmacologic agents that mimic steroid actions have a slow onset of effects, yet last a long time.

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