Figure 1. Oxytocin signaling pathway
The oxytocin signaling pathway refers to signaling pathway proteins including oxytocin, oxytocin receptors, and related regulatory factors. Oxytocin is a peptide hormone secreted by the posterior pituitary. Synthesized from the hypothalamic paraventricular nucleus and supraoptic nucleus, it consists of 9 amino acids. It is transported to the pituitary gland at a rate of 2 mm to 3 mm per day. The methionine residues at the "1" and "6" positions form a cyclic structure of a 6-peptide in the form of a disulfide bond. The physiological role of the oxytocin signaling pathway is mainly to stimulate the breast to secrete milk, promote the contraction of the uterine smooth muscle during childbirth, and promote the role of maternal love. In addition, it can reduce the level of stress hormones such as adrenal ketones in the body to lower blood pressure. It is not a woman's patent, and both men and women can secrete it. Its role is mainly in lactating mammary glands to continuously secrete milk under the action of prolactin and store it in the mammary gland. Oxytocin can contract the myoepithelial cells around the breast acinus and promote breast milk with lactation function; oxytocin has a strong promoting contraction effect on the uterus, but it is sensitive to the pregnant uterus.
The oxytocin signaling pathway initiates a subsequent response by the binding of oxytocin and the receptor. Oxytocin is composed of 9 amino acids, of which 2 cysteines form a disulfide bond at 1,6 positions with a relative molecular weight of 1,007, which exists as a free peptide in the blood circulation. The biological half-life of oxytocin is only 3 to 10 minutes, and the half-life is shorter at high concentrations. The metabolic clearance rate of the mother during pregnancy is 19-21 ml per kilogram of body weight, which is mainly cleared by the liver and discharged from the kidney in an inactive form. The oxytocin is also degraded by oxytocin in the uterus during pregnancy. Oxytocin is mainly synthesized in the large cells of the suprachiasmatic nucleus and paraventricular nucleus of the hypothalamus, and a small amount is synthesized in peripheral organs. The regulation mechanism is still not clear, and the regulatory sequences in the oxytocin gene are also unknown. The special anatomical structure of neurons makes oxytocin have a dual role of hormones and neurotransmitters. Neurosecretory granules containing oxytocin and pituitary vasopressin are widely distributed in Purkinje fibers and distributed along neurons. In addition, oxytocin is widely distributed in organs such as uterus, ovary, testis, adrenal gland, thymus, and pancreas, and has functions of autocrine and paracrine. The Oxytocin Receptor (OTR) belongs to the type A G-protein coupled receptor (GPCR) family and contains seven transmembrane alpha helices consisting of 389 amino acid residues. Oxytocin receptors can be coupled to subunits such as Gq, Gi1, Gi2, Gi3, GoA, and GoB, causing an increase in cytosolic calcium concentration (coupling to the Gq subunit) or inhibition of adenylate cyclase activity (coupling with the Gi subunit). The oxytocin receptor gene is located on human chromosome 3p25 and is about 19 kb in length, containing 3 introns and 4 exons. Because oxytocin has high sequence homology with another neuropeptide (vasopressin, AVP, also known as arginine vasopressin), when studying novel agonists and antagonists of the oxytocin system, vasopressin receptors (ie, V1a receptor and V2 receptor) are usually used as controls for examining whether the affinity of the novel ligand to the oxytocin receptor is significantly stronger than its affinity for the vasopressin receptor. The major region that mediates the binding of the oxytocin receptor and the vasopressin receptor to the corresponding ligand is in the third transmembrane region of the receptor, while the oxytocin receptor 5 and 6 transmembrane regions are specifically recognized by oxytocin. There are three different affinity oxytocin binding sites in the myometrium of rats. Among them, the binding site of the intermediate affinity is the oxytocin receptor, and the other two roles are still unclear. The low-affinity binding site has no obvious pharmacological effects. The high-affinity binding site is believed to interact with the central affinity binding site to affect the uterus. Upon binding to oxytocin or its agonist or antagonist, the receptor undergoes a change in affinity. Therefore, although the receptor density does not change, if the affinity of the receptor changes, the biological function and biological activity of the uterus can be affected. The human mesenteric oxytocin receptor has a relative molecular mass of about 43,000 and consists of 388 amino acids, presumably containing seven transmembrane peptides, like the G protein-binding receptor.
Oxytocin signaling pathway
Oxytocin promotes uterine contraction through the activation of calcium channels associated with receptors and the release of sarcoplasmic reticulum calcium. Oxytocin binds to the receptor and is mediated by a second messenger, which is regulated by voltage or hormone regulation on the muscle cell membrane and by contractor-mediated extracellular calcium influx. Oxytocin increases the production of inositol 1,4,5-triphosphate, and the mobilization of 5-trisphosphate inositol stores intracellular calcium release in the endoplasmic reticulum and sarcoplasmic reticulum. In addition, oxytocin also causes cells to produce inward currents through receptor-activated, non-selective cation channels that depolarize cell membranes, producing action potentials and muscle contractions. In vitro experiments on human uterine myocytes are derived from a term that pregnancy indicates that oxytocin affects uterine contractility through membrane potential depolarization but does not affect the interaction of muscle cells through gap junctions, indicating uterine muscle contraction and myocyte coordination. The mechanism of action is different. At present, the role of the second messenger cAMP and cGMP is not yet clear. In vitro studies have observed that cAMP is involved in an exponential increase in the number of amniotic oxytocin receptors during rabbit pregnancy. Oxytocin increases the activity of mitogen-activated protein kinases through the mediation of G-protein. Oxytocin also increases the activity of alanine aminotransferase and phospholipase C through the interaction of the oxytocin receptor with the Gα q and Gα 11 chains of the binding protein.
The genetic structure and genomic composition between oxytocin and vasopressin (VP) in the hypothalamus are closely related. They all have the same origin, all of which are small fragments of up to 2500 base pairs. The oxytocin gene consists of three exons and two inserts. Exon A includes a signal peptide, an oxytocin sequence portion, and an N-terminal portion of the vasopressin carrier protein. Exon B is the middle portion of the pituitary vasopressin, and exon C is the pituitrin, and carries the C-terminal portion of the protein. The human oxytocin and VP genes are located at the same position on chromosome 20, but the direction of transcription is reversed. The sequence between the two genes is 9 kb. The non-coding region at the 5' end of the transcriptional origin of the oxytocin gene in human, rat and female cattle is highly variable, with only a few pairs of nucleotide sequences being similar. The difference between the 5' end of the oxytocin and the VP gene is also large. There is also an oxytocin-specific enhancer in or near the VP gene, because the oxytocin gene can be expressed only when a small fragment is ligated to the VP gene. Estrogen increases the expression of the oxytocin gene in rat uterus and human amniotic, chorionic, and decidual cultures. The promoter region of the rat oxytocin gene contains two estrogen-responsive fragments, and the human gene contains only one gene. The reaction fragment requires only one gene fragment of -49 to +36 located in the 5' flanking region of the gene. However, the direct stimulatory effect of estrogen on the oxytocin gene may be limited to a subset of oxytocin neurons that bind to estrogen.
In recent years, studies on oxytocin and receptor genes and depression have provided new directions for the study of neurological mechanisms and clinical research of mental disorders such as depression. Moreover, oxytocin can improve the patient's depressive symptoms by regulating the therapeutic targets such as HPA axis and hippocampal neurogenesis, so oxytocin is likely to become a new drug for target treatment of depressed patients.
Autism is a widespread neurodevelopmental disorder of unknown causes, and there is no effective treatment to date. As one of the characteristic symptoms of autism, social disorders seriously affect the physical and mental health and quality of life of patients. Studies have shown that oxytocin plays an important role in social interactions, and oxytocin deficiency or underutilization may be associated with social disorders in autistic patients.
A study by Rubin et al. (2010) found that the higher the level of oxytocin in the peripheral nervous system of women with mental illness, the less clinical symptoms they have. Goldman, Marlow-O'Connor, Torres, and Carter (2008) collected oxytocin levels in the blood of normal and schizophrenia patients and found that oxytocin levels were positively correlated with facial expression recognition, whereas patients with low-sodium schizophrenia Oxytocin levels were significantly lower than normal sodium patients with schizophrenia and normal people. More interestingly, the researchers found that the levels of oxytocin in the blood of the normal group increased before and after the trust interaction of sharing secrets, while the schizophrenic group did not change.