Nuclear Receptor The fourth type of receptors we will consider belong to the nuclear receptor family. By the 1980s, it was clear that receptors for steroid hormones such as oestrogen and the glucocorticoids were present in the cytoplasm of cells and translocated into the nucleus after binding with their steroid partner. Other hormones, such as the thyroid hormone T3 and the fat-soluble vitamins D and A (retinoic acid) and their derivatives that regulate growth and development, were found to act in a similar fashion. Genome and protein sequence data revealed a close relationship between these receptors and led to the recognition that they were members of a much larger family of related proteins.

Today, it is convenient to regard the entire nuclear receptor family as ligand-activated transcription factors that transduce signals by modifying gene transcription. Unlike the other receptors, the nuclear receptors are not embedded in membranes but are present in the soluble phase of the cell. Some, such as the steroid receptors, become mobile in the presence of their ligand and can translocate from the cytoplasm to the nucleus, while others probably dwell mainly within the nuclear compartment. Pharmacologically, this entire family of nuclear receptors is very important. They regulate many drug metabolic enzymes and transporters and are responsible for the biological effects of approximately 10% of all prescription drugs. There are also many illnesses associated with malfunctioning of the nuclear receptor system, including inflammation, cancer, diabetes, cardiovascular disease, obesity and reproductive disorders.

Type of Nuclear receptor The nuclear receptor superfamily consist of two main classes-together with a third that shares some of the characteristics of both. Class I consists largely of receptors for the steroid hormones, including the glucocorticoid and mineralocorticoid receptors, as well as the oestrogen, progesterone and androgen receptors. In the absence of their ligand, these receptors are predominantly located in the cytoplasm, complexed with heat shock and other proteins and possibly reversibly attached to the cytoskeleton or other structures. Following diffusion (or possibly transportation) of their ligand partner into the cell and high-affinity binding, these receptors generally form homodimers and translocate to the nucleus, where they can transactivate or transrepress genes by binding to 'positive' or 'negative' hormone response elements.progesterone

Class II nuclear receptors function in a slightly different way. Their ligands are generally lipids already present to some extent within the cell. This group includes the peroxisome proliferator-activated receptor (PPAR) that recognises fatty acids; the liver oxysterol (LXR) receptor that recognises and acts as a cholesterol sensor, the farnesoid (bile acid) receptor (FXR), a xenobiotic receptor (SXR) that recognises a great many foreign substances, including therapeutic drugs, and the constitutive androstane receptor (CAR), which not only recognises the steroid androstane but also some drugs such as phenobarbital. Unlike the receptors in class I, these receptors almost always operate as heterodimers together with the retinoid receptor (RXR). They tend to mediate positive feedback effects (e.g. occupation of the receptor amplifies rather than inhibits a particular biological event).

A third group of nuclear receptors is really a subgroup of class II in the sense that they form obligate heterodimers with RXR, but rather than sensing lipids, they too play a part in endocrine signalling. The group includes the thyroid hormone receptor (TR), the vitamin D receptor (VDR) and the retinoic acid receptor (RAR).

Structure Most nuclear receptors are located in the nucleus and the ligands are all lipophilic compounds which can readily cross the cell membrane. The basic structure of this family of receptors is shown below.

The receptors are large monomeric proteins of residues, containing a highly conserved region of about 60 residues in the middle of the molecule which constitutes the DNA-binding domain of the receptor. It contains two loops of about 15 residues each (Zinc fingers), knotted together by a cluster of four cysteine residues surrounding a zinc atom: these structures occur in many proteins that regulate DNA transcription, and the fingers are believed to wrap around the DNA helix. The hormone-binding domain lies downstream of this central region, while upstream lies a variable region which is responsible controlling gene transcription.

Signal transduction On binding a steroid molecule, the receptor changes its conformation, which facilitates the formation of receptor dimers. These dimers bind to specific sequences of the nuclear DNA, known as hormone-responsive elements, and cause an increase RNA polymerase activity and the production of specific mRNA within a few minutes of adding the steroid.

For example, (i) Glucocorticoids inhibit transcription of the gene for cyclooxygenase-2 (COX-2), which may account for their anti- inflammatory properties. (ii) Mineralocorticoids stimulate the production of various transport proteins that are involved in the renal tubular function.

RECEPTORS AND DISEASE Increasing understanding of receptor function in molecular terms has revealed a number of disease states directly linked to receptor malfunction. The principal mechanisms involved are: autoantibodies directed against receptor proteins mutations in genes encoding receptors and proteins involved in signal transduction. An example of the former is myasthenia gravis, a disease of the neuromuscular junction due to autoantibodies that inactivate nicotinic acetylcholine receptors. Autoantibodies can also mimic the effects of agonists, as in many cases of thyroid hypersecretion, caused by activation of thyrotropin receptors. Activating antibodies have also been discovered in patients with severe hypertension (α-adrenoceptors), cardiomyopathy (β-adrenoceptors), and certain forms of epilepsy and neurodegenerative disorder (glutamate receptors).

Inherited mutations of genes encoding GPCRs account for various disease states. Mutated vasopressin and adrenocorticotrophic hormone receptors can result in resistance to these hormones.vasopressin Receptor mutations can result in activation of effector mechanisms in the absence of agonist. One of these involves the receptor for thyrotropin, producing continuous oversecretion of thyroid hormone. Mutations in G-proteins can also cause disease. For example, mutations of a particular Gα subunit cause one form of hypoparathyroidism, while mutations of a Gβ subunit result in hypertension. Many cancers are associated with mutations of the genes encoding growth factor receptors, kinases and other proteins involved in signal transduction.