AVP gene

The arginine vasopressin gene (AVP) is a gene whose product is proteolytically cleaved to produce vasopressin (also known as antidiuretic hormone or ADH), neurophysin II, and a glycoprotein called copeptin. AVP and other AVP-like peptides are found in mammals, as well as mollusks, arthropods, nematodes, and other invertebrate species.^[5] In humans, AVP is present on chromosome 20 and plays a role in homeostatic regulation. The products of AVP have many functions that include vasoconstriction, regulating the balance of water in the body, and regulating responses to stress.^[6] Expression of AVP is regulated by the transcription translation feedback loop (TTFL), which is an important part of the circadian system that controls the expression of clock genes. AVP has important implications in the medical field as its products have significant roles throughout body.

Discovery

Vasopressin

The discovery of the AVP gene first required the discovery of one of its key products: vasopressin. In 1895, G. Oliver and E.A. Schäfer found that a substance released by the pituitary gland could elevate blood pressure. The researchers noted that intravenous injection of extracts from the pituitary gland, thyroid gland, and spleen all influence blood pressure, however the effect from the pituitary had the most significant impact.^[7] Almost thirty years later, Kamm and colleagues separated the components within the pituitary gland. Using a unique, five-step separation technique, Kamm revealed one substance associated with uterine contractions – oxytocin – and another substance associated with blood pressure – vasopressin.^[8]

Once the discovery and separation of vasopressin occurred, subsequent research on the product's structure, function, and mode of generation could take place. In 1951, Turner and colleagues uncovered the amino acid sequence behind the hormone. The amino acid structure was composed of eight amino acids, including phenylalanine, tyrosine, proline, glutamic acid, aspartic acid, glycine, arginine, and cystine. The structure was also found to include ammonia.^[9] Following this discovery, Vincent du Vigneaud was able to synthesize a synthetic form of vasopressin in a laboratory setting. Du Vigneaud specifically noted that his final product had the same activity and composition ratios as that of naturally occurring vasopressin.^[10]

AVP gene

The work on vasopressin ultimately allowed researchers to work backwards and identify the gene responsible for this product's generation. This final stage of research began when Gainer and colleagues found a precursor protein to vasopressin in 1977.^[11] The structure of the protein was subsequently discovered by Land in 1982. By sequencing complementary DNA strands that encoded for the hormone's mRNA, Land outlined the amino acid sequence of the precursor protein.^[12] Finally, one year later, Schmale, Heinsohn, and Richter isolated the AVP precursor gene in rats from their genomic library. The researchers used restriction mapping and nucleotide sequence analysis to uncover the gene's three distinct exons and the products (vasopressin, neurophysin, and glycoprotein) that each was responsible for.^[13]

Structure

The 1.85 kilobase-long AVP gene, located on chromosome 20 (20p13) contains three functional domains, including AVP, neurophysin II (NP) and a C-terminal glycopeptide called copeptin. Using restriction mapping and sequencing, the gene was found to have these domains which spanned over three exons with two intronic sequences. Exon A encodes a putative signal peptide, the arginine vasopressin hormone, and the N terminus of the NP carrier protein. Exon B, which is separated from exon A with a 1 kilobase-long intron, encodes the conserved middle portion of NP. A 227 kilobase intron separates exon B from exon C, which encodes the final domain, including the C terminus of NP and the glycoprotein. The structure of this gene has been found to be generally conserved across species, including chimpanzees, Rhesus monkeys, dogs, cows, mice, rats, chicken, zebrafish, and frogs.^[13]

Promoter region

The AVP gene promoter region consists of an

Transcription of the AVP gene to produce AVP mRNA has daily rhythms, with mRNA levels peaking during the subjective day and reaching their lowest point in the subject night. This rhythm is regulated by the binding of circadian proteins to the E-box, along with transcriptional regulation of other elements, including the CRE in the promoter region.[14]

Function

AVP is primarily known for its role as a mammalian circadian output.^[15][17] The most common product of AVP is vasopressin, which is a neurohypophysial hormone that is important in homeostatic mechanisms and processes, like cortical EEG rhythms. Its other products are neurophysin II and copeptin. AVP is produced in a specific type of neuron called magnocellular neurons (MCNs), which are located in the hypothalamus.^[17] In mammals, the AVP gene is also transcribed in the suprachiasmatic nucleus where its expression is under the control of the circadian TTFL.^[18] It is well established that the finished vasopressin product is transported from the cell body to the terminals in the posterior pituitary gland where it is released into the bloodstream as a result of environmental stressors like dehydration.^[19]

Gene regulation

AVP gene regulation is controlled by the TTFL. In this system,

Within rats, the AVP gene is important for the regulation of various processes associated with the excretory system and smooth muscle cells. The AVP gene and arginine vasopressin are commonly colocalized with oxytocin because synaptic transmission of oxytocin regulates the expression of AVP mRNA.^[26]

In one study conducted by Greenwood and colleagues, researchers found that AVP gene expression in rats is regulated by the cAMP responsive element-binding protein-3 like-1 (CREB3L1). CREB3L1 is activated when it is cleaved and when the AVP gene is translocated from the Golgi to the nucleus.^[27] Additionally, CREB3L1 mRNA levels correspond with increased amounts of transcription of the AVP gene in the hypothalamus following a deficiency of sodium and as a consequence of diurnal rhythm in the SCN.^[27] Both full-length and constitutively active forms of CREB3L1 (CREB3L1CA) induce the expression of rat AVP promoter-luciferase reporter constructs whereas a dominant-negative mutant reduces expression. From this study, the researchers concluded that CREB3L1 is a regulator of AVP gene transcription in the hypothalamus and specifically within the PVH and SON.

Arginine vasopressin stimulates the process of

The functions of vasopressin make it useful for a variety of important medical applications. Since it plays a role in the regulation of many physiological functions, like regulation of water and sodium excretion, blood volume, vasoconstriction, and response to stress, vasopressin can be helpful in the treatment of conditions related to these functions.^[29] These applications include treatment of nocturnal enuresis, diabetes insipidus, and hemophilia A.^[30] Additionally, it is used to treat some forms of shock including septic shock and vasodilatory shock. It is also used during surgery to decrease blood loss.^[31]  

References