Nuclear Receptors

Nuclear receptors are ligand-activated transcription factors that bind nonpolar regulatory molecules. Because ligands are nonpolar, they can just diffuse across the plasma membrane to bind to the nuclear receptor that is an intracellular receptor.  Nuclear receptor ligands include steroid hormones, thyroid hormones, retinoic acid, and vitamin D3, but also fatty acids and phospholipids.

The DNA sequences for two steroid hormone receptors (the glucocorticoid receptor and the estrogen receptor) were first determined in the mid-1980s. The structural homology between these two receptors caused investigators to hypothesize that they were part of a family of proteins. Subsequently, more members of the family were cloned based on sequence homology. There are a total of 48 nuclear receptor family members in the human genome. For some of these receptors, the physiological function and endogenous natural ligand are not known: these are termed orphan receptors.  Some of the original orphan receptors have now had their endogenous ligands identified ("adopted orphans").  An important group of receptors in this class are the PPAR receptors, which are involved in metabolic regulation, and are important drug targets.  Fibrates (which bind to the receptor PPAR-alpha) are a class of drugs used to treat dyslipidemia in order to lower the risk of cardiovascular disease.  Thiazolidinediones (TZDs; which bind to the receptor PPAR-gamma) are drugs that promote insulin sensitivity in the treatment of type 2 diabetes mellitus.

The basic molecular structure of a nuclear receptor is shown in a linear form in the figure below.  All the nuclear receptors contain three important domains:  a transcriptional regulation domain, a DNA binding domain, and a ligand binding domain.

This next figure diagrams how signaling works for many nuclear receptors.

In the absence of ligand, an inhibitory complex associates with the ligand-binding domain.  Ligand binding causes a conformational change so that the inhibitory complex (red) dissociates.  This allows the receptor to bind to DNA, and associate with the coregulator protein complex (green), a group of proteins that regulate gene transcription.  Genes that are regulated by nuclear receptors contain particular DNA sequences (response elements) in their promoters, where the nuclear receptor binds. 

The coregulator proteins that associate with the receptor may be activators or repressors of transcription.   One particular receptor may associate with different groups of coregulators in different cell types. This differential recruitment of coregulators is thought to underlie the action of drugs known as receptor modulators. Receptor modulators are drugs that act as agonists in some tissues, while acting as antagonists in other tissues. An example is the selective estrogen receptor modulator (SERM) known as raloxifene. Raloxifene is used to prevent loss of bone density in postmenopausal women. Raloxifene acts as an estrogen receptor agonist in bone tissue, but acts as an estrogen receptor antagonist in breast and uterine tissue.

Quick Quiz

Fill in Answer Correct False Correct Answer
1. What kind of molecule binds to a nuclear receptor? [polar; nonpolar; ion]
2. ALL of the following are ligands for nuclear receptors EXCEPT _______. [phospholipid, steroid hormone, peptide hormone, thyroid hormone, fatty acid]
3. A receptor whose natural endogenous ligand is not known is called an ____________.
4. Nuclear receptors are ligand-activated ________________.
5. A drug that can work as an agonist in some tissues and an antagonist in others is called a ___________________.
6. What is the name for the specific sequence in the DNA where the nuclear receptor binds?

(Spelling must be correct)