Androgen receptor

The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor which is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone. The main function of the androgen receptor is as a DNA binding transcription factor which regulates gene expression. However the androgen receptor also has additional functions independent of DNA binding

The androgen receptor is most closely related to the progesterone receptor, and progestins in higher dosages can block the androgen receptor.

Structure
Two isoforms of the androgen receptor (A and B) have been identified:
 * AR-A -  87 kDa - N-terminus truncated (lacks the first 187 amino acids)
 * AR-B - 110 kDa - full length

Domains
Like other nuclear receptors, the androgen receptor is modular in structure and is comprised of the following functional domains labeled A through F:
 * A/B) - N-terminal regulatory domain contains:
 * activation function 1 (AF-1) between residues 101 and 370 required for full ligand activated transcriptional activity
 * activation function 5 (AF-5) between residues 360-485 is responsible for the constitutively activity (activity without bound ligand)
 * dimerization surface involving residues 1-36 (containing the FXXLF motif where F = phenylalanine, L = leucine, and X = any amino acid residue) and 370-494 which both interact with the LBD in an unusual (for a nuclear receptor) head-to-tail interaction
 * C) - DNA binding domain (DBD)
 * D) - Hinge region - flexible region that connects the DBD with the LBD; influences subcellular trafficking
 * E) - Ligand binding domain (LBD) containing
 * activation function 2 (AF-2), responsible for agonist induced activity (activity in the presence of bound agonist)
 * AF-2 binds both coactivator proteins (containing the LXXLL motif) and/or the AF-1 region of another molecule of androgen receptor (containing the FXXLF motif) to form a head-to-tail dimer
 * F) - C-terminal domain

Gene
The gene for the androgen receptor is located on the X chromosome at Xq11-12.

Genomic
In some cell types testosterone interacts directly with androgen receptors while in others testosterone is converted by 5-alpha-reductase to dihydrotestosterone, an even more potent agonist for androgen receptor activation. Testosterone appears to be the primary androgen receptor activating hormone in the Wolffian duct while dihydrotestosterone is the main androgenic hormone in the urogenital sinus, urogenital tubercle, and hair follicles.

The primary mechanism of action for androgen receptors is direct regulation of gene transcription. The binding of an androgen to the androgen receptor results in a conformational change in the receptor which in turn causes dissociation of heat shock proteins, dimerization, and transport from the cytosol to the cell nucleus where the androgen receptor dimer binds to a specific sequence of DNA known as a hormone response element. Androgen receptors interact with other proteins in the nucleus resulting in up or down regulation of specific gene transcription. Up-regulation or activation of transcription results in increased synthesis of messenger RNA which in turn is transcribed by ribosomes to produce specific proteins. One of the known target genes of androgen receptor activation is insulin-like growth factor I (IGF-1). Thus, changes in levels of specific proteins in cells is one way that androgen receptors control cell behavior.

Androgens cause slow epiphysis, or maturation of the bones, but more of the potent epiphysis effect comes from the estrogen produced by aromatization of androgens. Steroid users of teen age may find that their growth had been stunted by androgen and/or estrogen excess. People with too little sex hormones can be short during puberty but end up taller as adults as in androgen insensitivity syndrome or estrogen insensitivity syndrome.

Non-genomic
More recently, androgen receptors have been shown to have a second mode of action. As has been also found for other steroid hormone receptors such as estrogen receptors, androgen receptors can have actions that are independent of their interactions with DNA. Androgen receptors interact with certain signal transduction proteins in the cytoplasm. Androgen binding to cytoplasmic androgen receptors can cause rapid changes in cell function independent of changes in gene transcription, such as changes in ion transport. Regulation of signal transduction pathways by cytoplasmic androgen receptors can indirectly lead to changes in gene transcription, for example, by leading to phosphorylation of other transcription factors.

One function of androgen receptor that is independent of direct binding to its target DNA sequence, is facilitated by recruitment via other DNA binding proteins. One example is Serum Response Factor, a protein which activates several genes that cause muscle growth.

AR deficiencies
The androgen insensitivity syndrome, formerly known as testicular feminization, is caused by a mutation of the Androgen Receptor gene located on the X chromosome (locus:Xq11-Xq12). The androgen receptor seems to affect neuron physiology and is defective in Kennedy disease.