Glucocorticoid receptor
Encyclopedia
The glucocorticoid receptor (GR, or GCR) also known as NR3C1 (nuclear receptor
subfamily 3, group C, member 1) is the receptor to which cortisol
and other glucocorticoids bind.
The GR is expressed in almost every cell in the body and regulates gene
s controlling the development
, metabolism
, and immune response
. Because the receptor gene is expressed in several forms, it has many different (pleiotropic) effects in different parts of the body.
When the GR binds to glucorticoids, its primary mechanism of action is the regulation of gene transcription. The unbound receptor resides in the cytosol
of the cell (the part of the cell outside of the nucleus
). After the receptor is bound to glucocorticoid, the receptor-glucorticoid complex can take either of two paths. The activated GR complex up-regulates the expression of anti-inflammatory proteins in the nucleus or represses the expression of pro-inflammatory proteins in the cytosol (by preventing the translocation of other transcription factor
s from the cytosol into the nucleus).
In humans, the GR protein is encoded by NR3C1 gene
which is located on chromosome 5
(5q31).
90 (hsp90
), the heat shock protein 70 (hsp70
) and the protein FKBP52
(FK506-binding protein 52). The endogenous glucocorticoid hormone cortisol
diffuses through the cell membrane
into the cytoplasm
and binds to the glucocorticoid receptor (GR) resulting in release of the heat shock proteins. The resulting activated form GR has two principal mechanisms of action, transactivation and transrepression, described below.
, and binding to specific DNA responsive elements activating gene transcription
. This mechanism of action is referred to as transactivation
. The biologic response depends on the cell type.
themselves are able to transactivate target genes. However activated GR can complex with these other transcription factors and prevent them from binding their target genes and hence repress the expression of genes that are normally upregulated by NF-κB or AP-1. This indirect mechanism of action is referred to as transrepression
.
In Central Nervous System
structures, the glucocorticoid receptor is gaining interest as a novel representative of neuroendocrine integration, functioning as a major component of endocrine influence - specifically the stress response - upon the brain. The receptor is now implicated in both short and long-term adaptations seen in response to stressors and may be critical to the understanding of psychological disorders, including some or all subtypes of depression. Indeed, long-standing observations such as the mood dysregulations typical of Cushing's disease
demonstrate the role of corticosteroids in regulating psychologic state; recent advances have demonstrated interactions with norepinephrine
and serotonin
at the neural level.
is an agonist, and RU486 and cyproterone
are antagonists of the GR. Also, progesterone
and DHEA have antagonist effects on the GR.
with:
Nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...
subfamily 3, group C, member 1) is the receptor to which cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
and other glucocorticoids bind.
The GR is expressed in almost every cell in the body and regulates gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s controlling the development
Developmental biology
Developmental biology is the study of the process by which organisms grow and develop. Modern developmental biology studies the genetic control of cell growth, differentiation and "morphogenesis", which is the process that gives rise to tissues, organs and anatomy.- Related fields of study...
, metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
, and immune response
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. Because the receptor gene is expressed in several forms, it has many different (pleiotropic) effects in different parts of the body.
When the GR binds to glucorticoids, its primary mechanism of action is the regulation of gene transcription. The unbound receptor resides in the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
of the cell (the part of the cell outside of the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
). After the receptor is bound to glucocorticoid, the receptor-glucorticoid complex can take either of two paths. The activated GR complex up-regulates the expression of anti-inflammatory proteins in the nucleus or represses the expression of pro-inflammatory proteins in the cytosol (by preventing the translocation of other transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s from the cytosol into the nucleus).
In humans, the GR protein is encoded by NR3C1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
which is located on chromosome 5
Chromosome 5 (human)
Chromosome 5 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 5 spans about 181 million base pairs and represents almost 6% of the total DNA in cells. Chromosome 5 is one of the largest human chromosomes, yet has one of the lowest gene...
(5q31).
Structure
Like the other steroid receptors, the glucocorticoid receptor is modular in structure and contains the following domains (labeled A - F):- A/B - N-terminal regulatory domain
- C - DNA-binding domainDNA-binding domainA DNA-binding domain is an independently folded protein domain that contains at least one motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence or have a general affinity to DNA...
(DBD) - D - hinge region
- E - ligand-binding domain (LBD)
- F - C-terminal domain
Ligand binding and response
In the absence of hormone, the glucocorticoid receptor (GR) resides in the cytosol complexed with a variety of proteins including heat shock proteinHeat shock protein
Heat shock proteins are a class of functionally related proteins involved in the folding and unfolding of other proteins. Their expression is increased when cells are exposed to elevated temperatures or other stress. This increase in expression is transcriptionally regulated...
90 (hsp90
Hsp90
Hsp90 is a molecular chaperone and is one of the most abundant proteins expressed in cells. It is a member of the heat shock protein family, which is upregulated in response to stress...
), the heat shock protein 70 (hsp70
Hsp70
The 70 kilodalton heat shock proteins are a family of ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms...
) and the protein FKBP52
FKBP52
FK506-binding protein 4 is a protein that in humans is encoded by the FKBP4 gene.This protein contains TPR repeats and has a PPlase domain.-Further reading:-External links:...
(FK506-binding protein 52). The endogenous glucocorticoid hormone cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
diffuses through the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
into the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
and binds to the glucocorticoid receptor (GR) resulting in release of the heat shock proteins. The resulting activated form GR has two principal mechanisms of action, transactivation and transrepression, described below.
Transactivation
A direct mechanism of action involves homodimerization of the receptor, translocation via active transport into the nucleusCell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
, and binding to specific DNA responsive elements activating gene transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
. This mechanism of action is referred to as transactivation
Transactivation
In molecular biology and genetics, transactivation is an increased rate of gene expression triggered either by biological processes or by artificial means.- Natural transactivation :...
. The biologic response depends on the cell type.
Transrepression
In the absence of activated GR, other transcription factors such as NF-κB or AP-1AP-1 (transcription factor)
In the field of molecular biology, the activator protein 1 is a transcription factor which is a heterodimeric protein composed of proteins belonging to the c-Fos, c-Jun, ATF and JDP families. It regulates gene expression in response to a variety of stimuli, including cytokines, growth factors,...
themselves are able to transactivate target genes. However activated GR can complex with these other transcription factors and prevent them from binding their target genes and hence repress the expression of genes that are normally upregulated by NF-κB or AP-1. This indirect mechanism of action is referred to as transrepression
Transrepression
In the field of molecular biology, transrepression is a process whereby one protein represses the activity of a second protein through a protein-protein interaction...
.
Clinical significance
The GR is abnormal in familial glucocorticoid resistance.In Central Nervous System
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
structures, the glucocorticoid receptor is gaining interest as a novel representative of neuroendocrine integration, functioning as a major component of endocrine influence - specifically the stress response - upon the brain. The receptor is now implicated in both short and long-term adaptations seen in response to stressors and may be critical to the understanding of psychological disorders, including some or all subtypes of depression. Indeed, long-standing observations such as the mood dysregulations typical of Cushing's disease
Cushing's disease
Cushing's disease is a cause of Cushing's Syndrome characterised by increased secretion of adrenocorticotropic hormone from the anterior pituitary. This is most often as a result of a pituitary adenoma...
demonstrate the role of corticosteroids in regulating psychologic state; recent advances have demonstrated interactions with norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
and serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
at the neural level.
Agonists and antagonists
DexamethasoneDexamethasone
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
is an agonist, and RU486 and cyproterone
Cyproterone
Cyproterone acetate is an antiandrogen...
are antagonists of the GR. Also, progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
and DHEA have antagonist effects on the GR.
Interactions
Glucocorticoid receptor has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with:
- BAG1BAG1BAG family molecular chaperone regulator 1 is a protein that in humans is encoded by the BAG1 gene.BAG gene has been implicated in age related neurodegenerative diseases as Alzheimer's...
, - CEBPBCEBPBCCAAT/enhancer-binding protein beta is a protein that in humans is encoded by the CEBPB gene.- Function :The protein encoded by this intronless gene is a bZIP transcription factor that can bind as a homodimer to certain DNA regulatory regions. It can also form heterodimers with the related proteins...
, - CREBBP,
- DAP3DAP328S ribosomal protein S29, mitochondrial is a protein that in humans is encoded by the DAP3 gene.-Interactions:DAP3 has been shown to interact with FADD, TNFRSF10A, Glucocorticoid receptor and Heat shock protein 90kDa alpha , member A1....
, - DAXXDeath associated protein 6Death-associated protein 6 also known as DAXX is a protein that in humans is encoded by the DAXX gene.- Function :DAXX, a death-domain-associated protein, was first discovered through its cytoplasmic interaction with the classical death receptor Fas...
, - HSP90AA1,
- HNRPUHNRPUHeterogeneous nuclear ribonucleoprotein U is a protein that in humans is encoded by the HNRNPU gene.-Interactions:HNRPU has been shown to interact with NDN, EP300, Glucocorticoid receptor and GTF2F1.-Further reading:...
, - MED1MED1Mediator of RNA polymerase II transcription subunit 1 is a protein that in humans is encoded by the MED1 gene.- Function :The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer sites in DNA. These factors work with...
, - MED14MED14Mediator of RNA polymerase II transcription subunit 14 is an enzyme that in humans is encoded by the MED14 gene.-Interactions:MED14 has been shown to interact with PPARGC1A, Estrogen receptor alpha, STAT2, Cyclin-dependent kinase 8, Glucocorticoid receptor and Hepatocyte nuclear factor 4...
, - Mineralocorticoid receptorMineralocorticoid receptorThe mineralocorticoid receptor , also known as the aldosterone receptor or nuclear receptor subfamily 3, group C, member 2, is a protein that in humans is encoded by the NR3C2 gene that is located on chromosome 4q31.1-31.2.MR is a receptor with high affinity for mineralocorticoids...
, - NRIP1NRIP1Nuclear receptor-interacting protein 1 is a protein that in humans is encoded by the NRIP1 gene.RIP140 has an important role in regulating lipid and glucose metabolism, and regulates gene expression in metabolic tissues including heart, skeletal muscle, and liver.Knockout mice that completely lack...
, - NCOR1Nuclear receptor co-repressor 1The nuclear receptor co-repressor 1 also known as thyroid-hormone- and retinoic-acid-receptor-associated co-repressor 1 is a protein that in humans is encoded by the NCOR1 gene....
, - NCOA1Nuclear receptor coactivator 1The nuclear receptor coactivator 1 is a transcriptional coregulatory protein that contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity . NCOA1 is recruited to DNA promotion sites by ligand-activated nuclear receptors. NCOA1, in turn, acylates...
, - NCOA2Nuclear receptor coactivator 2The nuclear receptor coactivator 2 is a transcriptional coregulatory protein which contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity. NCOA2 is recruited to DNA promotion sites by ligand activated nuclear receptors. NCOA2 in turn acylates...
, - NCOA3Nuclear receptor coactivator 3The nuclear receptor coactivator 3 also known as NCOA3 is a protein that, in humans, is encoded by the NCOA3 gene. NCOA3 is also frequently called 'amplified in breast 1' , steroid receptor coactivator-3 , or thyroid hormone receptor activator molecule 1 .-Function:NCOA3 is a transcriptional...
, - POU2F1POU2F1POU domain, class 2, transcription factor 1 is a protein that in humans is encoded by the POU2F1 gene.-Interactions:POU2F1 has been shown to interact with SNAPC4, Ku80, Glucocorticoid receptor, Sp1 transcription factor, NPAT, POU2AF1, Host cell factor C1, TATA binding protein, RELA, Nuclear...
, - RANBP9RANBP9Ran-binding protein 9 is a protein that in humans is encoded by the RANBP9 gene.-Interactions:RANBP9 has been shown to interact with C-Met, DYRK1B, USP11, DISC1, Androgen receptor, Glucocorticoid receptor, S100A7, HIPK2 and MKLN1.-Further reading:...
, - RELARELATranscription factor p65 is a protein that in humans is encoded by the RELA gene.-Interactions:RELA has been shown to interact with NFKBIB, ETHE1, NFKBIE, RFC1, TRIB3, CREB binding protein, Neutrophil cytosolic factor 1, Glucocorticoid receptor, MTPN, BRCA1, C-Fos, POU2F1, BTRC, TATA-binding...
, - SMAD3Mothers against decapentaplegic homolog 3Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene. SMAD3 is a member of the SMAD family of proteins.The human SMAD3 gene is located on chromosome 15...
, - SMARCD1SMARCD1SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 is a protein that in humans is encoded by the SMARCD1 gene.-Interactions:SMARCD1 has been shown to interact with Glucocorticoid receptor.-Further reading:...
, - SMARCA4SMARCA4Transcription activator BRG1 also known as ATP-dependent helicase SMARCA4 is a protein that in humans is encoded by the SMARCA4 gene.- Function :...
- STAT3STAT3Signal transducer and activator of transcription 3 also known as STAT3 is a transcription factor which in humans is encoded by the STAT3 gene.- Function :The protein encoded by this gene is a member of the STAT protein family...
, - STAT5BSTAT5BSignal transducer and activator of transcription 5B is a protein that in humans is encoded by the STAT5B gene. STAT5B orthologs have been identified in most placentals for which complete genome data are available.-Interactions:...
, - ThioredoxinThioredoxinThioredoxin is a class of small redox proteins known to be present in all organisms. It plays a role in many important biological processes. In humans, it is encoded by the TXN gene. Loss-of-function mutation of either of the two human thioredoxin genes is lethal at the four-cell stage of the...
, - TRIM28TRIM28Tripartite motif-containing 28 also known as transcriptional intermediary factor 1β is a protein that in humans is encoded by the TRIM24 gene.- Function :...
, and - YWHAHYWHAH14-3-3 protein eta is a protein that in humans is encoded by the YWHAH gene.-Interactions:YWHAH has been shown to interact with TNFAIP3, KLC3, C-Raf, Phosphoinositide-dependent kinase-1, RIMS2, KIF5B, RIMS1, CDC25B, ZFP36, EPB41L3, Glucocorticoid receptor and TLX2.-Further reading:...
.
See also
- Familial/sporadic glucocorticoid resistance (Chrousos Syndrome)
- Selective glucocorticoid receptor agonistSelective glucocorticoid receptor agonistA selective glucocorticoid receptor agonist , sometimes called a dissociated glucocorticoid receptor agonist , is a type of experimental drug that is designed to share many of the desirable anti-inflammatory and immunosuppressive properties of classical glucocorticoid drugs but with fewer side...
(SEGRA)