Corticotropin-releasing hormone receptor 1 (CRHR1) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

, also known as CRF₁, with the latter (CRF₁) now being the

IUPHAR The International Union of Basic and Clinical Pharmacology (IUPHAR) is a voluntary, non-profit association representing the interests of scientists in pharmacology-related fields to facilitate ''Better Medicines through Global Education and Resear ...

-recommended name. In humans, CRF₁ is encoded by the ''CRHR1''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

at region 17q21.31, beside micrototubule-associated protein tau

MAPT The tau proteins (abbreviated from tubulin associated unit) are a group of six highly soluble protein isoforms produced by alternative splicing from the gene ''MAPT'' (microtubule-associated protein tau). They have roles primarily in maintaining ...

Structure

The human CRHR1 gene contains 14

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...

s over 20 kb of DNA, and its full

gene product A gene product is the biochemical material, either RNA or protein, resulting from expression of a gene. A measurement of the amount of gene product is sometimes used to infer how active a gene is. Abnormal amounts of gene product can be correlate ...

is a

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

composed of 444

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

s. Excision of exon 6 yields in the

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...

for the primary functional CRF₁, which is a peptide composed of 415 amino acids, arranged in seven

hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, ...

alpha-helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...

. The CRHR1 gene is alternatively

spliced Spliced may refer to: *Spliced, the result of rope splicing Rope splicing in ropework is the forming of a semi-permanent joint between two ropes or two parts of the same rope by partly untwisting and then interweaving their strands. Splices ca ...

into a series of variants. These variants are generated through deletion of one of the 14 exons, which in some cases causes a

frame-shift A frameshift mutation (also called a framing error or a reading frame shift) is a genetic mutation caused by indels ( insertions or deletions) of a number of nucleotides in a DNA sequence that is not divisible by three. Due to the triplet nature ...

in the

open reading frame In molecular biology, open reading frames (ORFs) are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible readi ...

, and encode corresponding

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...

of CRF₁. Though these

have not been identified in native tissues, the

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...

s of the splice variants of mRNA suggest the existence of alternate CRF receptors, with differences in

intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

loops or deletions in

N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

transmembrane domain A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs generally adopt an alpha helix topological conformation, although some TMDs such as those in porins can adopt a different conformation. Because the interior of the lipid bi ...

s. Such structural changes suggest that the alternate CRF₁ receptors have different degrees of capacity and efficiency in binding CRF and its agonists. Though the functions of these CRF₁ receptors is yet unknown, they are suspected to be biologically significant. CRF₁ is 70% homologous with the second human CRF receptor family, CRF₂; the greatest divergence between the two lies at the

of the protein.

Mechanism of activation

CRF₁ is activated through the binding of CRF or a CRF-

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...

. The

ligand binding In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a mo ...

and subsequent receptor

conformational change In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors. A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or oth ...

depends on three different sites in the second and third

extracellular domain An ectodomain is the Protein domain, domain of a Cell membrane, membrane protein that extends into the extracellular space (the space outside a cell (biology), cell). Ectodomains are usually the parts of proteins that initiate contact with surfaces ...

s of CRF₁. In the majority of tissues, CRF₁ is coupled to a stimulatory G-protein that activates the

adenylyl cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...

signaling pathway, and ligand-binding triggers an increase in

cAMP Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...

levels. However, the signal can be transmitted along multiple

signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...

cascades, according to the structure of the receptor and the region of its expression. Alternate signaling pathways activated by CRF₁ include PKC and

MAPK A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...

. This wide variety of cascades suggests that CRF₁ mediates tissue-specific responses to CRF and CRF-

Tissue distribution

CRF₁ is expressed widely throughout both the

central Central is an adjective usually referring to being in the center of some place or (mathematical) object. Central may also refer to: Directions and generalised locations * Central Africa, a region in the centre of Africa continent, also known a ...

and

peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brai ...

s. In the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

, CRF₁ is particularly found in the

cortex Cortex or cortical may refer to: Biology * Cortex (anatomy), the outermost layer of an organ ** Cerebral cortex, the outer layer of the vertebrate cerebrum, part of which is the ''forebrain'' *** Motor cortex, the regions of the cerebral cortex i ...

cerebellum The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebe ...

amygdala The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex ver ...

hippocampus The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic syste ...

olfactory bulb The olfactory bulb (Latin: ''bulbus olfactorius'') is a neural structure of the vertebrate forebrain involved in olfaction, the sense of smell. It sends olfactory information to be further processed in the amygdala, the orbitofrontal cortex ...

ventral tegmental area The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is the ...

brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is ...

areas, paraventricular hypothalamus, and

pituitary In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The hypoph ...

. In the

, CRF₁ stimulation triggers the activation of the

POMC Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior pituitary from the 267-amino-acid-long polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the re ...

gene, which in turn causes the release of

ACTH Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important c ...

and β-endorphins from the

anterior pituitary A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the pit ...

. In the

, CRF₁ is expressed at low levels in a wide variety of tissues, including the

skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...

spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .

heart The heart is a muscular Organ (biology), organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as ca ...

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...

adipose tissue Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular ...

placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...

ovary The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. ...

testis A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testostero ...

, and

adrenal gland The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex ...

. In CRF₁

knockout mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...

, and mice treated with a CRF₁

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, ri ...

, there is a decrease in anxious behavior and a blunted

stress response The fight-or-flight or the fight-flight-or-freeze response (also called hyperarousal or the acute stress response) is a physiological reaction that occurs in response to a perceived harmful event, attack, or threat to survival. It was first des ...

, suggesting that CRF₁ mechanisms are

anxiogenic An anxiogenic or panicogenic substance is one that causes anxiety. This effect is in contrast to anxiolytic agents, which inhibits anxiety. Together these categories of psychoactive compounds may be referred to as anxiotropic compounds. Anxiogeni ...

. However, the effect of CRF₁ appears to be regionally specific and cell-type specific, likely due to the wide variety of cascades and signaling pathways activated by the binding of CRF or CRF-

s. In mice, offspring born to CRF₁ -/- knockout mothers typically die within a few days of birth from lung dysplasia, likely due to low glucocorticoid levels. In the

, CRF₁ activation mediates fear learning and consolidation in the extended

, stress-related modulation of

memory formation Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembered, ...

in the

, and

regulation of

arousal Arousal is the physiological and psychological state of being awoken or of sense organs stimulated to a point of perception. It involves activation of the ascending reticular activating system (ARAS) in the brain, which mediates wakefulness, th ...

Function

The corticotropin-releasing hormone receptor binds corticotropin-releasing hormone, a potent mediator of endocrine, autonomic, behavioral, and immune responses to stress. CRF1 receptors in mice mediate ethanol enhancement of GABAergic synaptic transmission.

Postpartum function

Postpartum CRF₁ knockout mice spend less time nursing and less time licking and grooming their offspring than their wildtype counterparts during the first few days postpartum. These pups weighed less as a result. This pattern of maternal behavior indicates that CRF₁ may be needed for early postpartum mothers to display typical mothering behaviors. Maternal aggression is attenuated by increases in CRF and urocortin 2, which bind to CRF₁.

Evolution

Corticotrophin releasing hormone (CRH) evolved ~ in an organism that subsequently gave rise to both

chordate A chordate () is an animal of the phylum Chordata (). All chordates possess, at some point during their larval or adult stages, five synapomorphies, or primary physical characteristics, that distinguish them from all the other taxa. These fi ...

s and

arthropod Arthropods (, (gen. ποδός)) are invertebrate animals with an exoskeleton, a segmented body, and paired jointed appendages. Arthropods form the phylum Arthropoda. They are distinguished by their jointed limbs and cuticle made of chiti ...

s.Lovejoy D, Chang B, Lovejoy N, Del Castillo J (2014) Origin and functional evolution of the corticotrophin-releasing hormone receptors. J Mol Endocrinol The binding site for this was single CRH like receptor. In vertebrates this gene was duplicated leading to the extant CRH1 and CRH2 forms. Additionally four paralogous ligands developed including CRH, urotensin-1/

urocortin Urocortin is a protein that in humans is encoded by the ''UCN'' gene. Urocortin belongs to the corticotropin-releasing factor (CRF) family of proteins which includes CRF, urotensin I, sauvagine, urocortin II and urocortin III. Urocortin is in ...

urocortin II Urocortin 2 (Ucn2) is an endogenous peptide in the corticotrophin-releasing factor (CRF) family. Urocortin II is a 38-amino acid peptide that is a member of the CRF family of peptides. Unlike Urocortin I, Urocortin II is highly selective for th ...

and

urocortin III Urocortin III is a 38 amino acid peptide that is a member of the CRF family of peptides. Unlike Urocortin I, and similar to Urocortin II, Urocortin III is highly selective for the CRF2 receptor and does not show affinity for the CRF binding prot ...

Clinical significance

Variations in the ''CRHR1'' gene is associated with enhanced response to inhaled

corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are inv ...

therapy in

asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...

. CRF1 triggers cells to release hormones that are linked to stress and anxiety riginal reference missing Hence CRF1 receptor antagonists are being actively studied as possible treatments for depression and anxiety. Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn.

Interactions

Corticotropin-releasing hormone receptor 1 has been shown to

interact Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex trai ...

with Corticotropin-releasing hormone and

References

External links

* * * * {{NLM content G protein-coupled receptors Corticotropin-releasing hormone