Regulatory peptides are responsible for the transfer of information within the tissues and the cells, between different organisms, and between the various organs of the body. These peptides are produced by all species of life, ranging from mammals to bacteria. So far, these peptides have shown signs and indications to be among the most diverse signaling molecules of all the molecules ever discovered in this category.
They have a broad spectrum of biological effects, with the most notable ones being their ability to act as hormones, pheromones, growth factors, neurotransmitters, and antibiotics, among others. Within the animal world, regulatory peptides affect a variety of physiological activities, including renal, cardiovascular, immune, and respiratory functions, among others. They are also greatly involved in a variety of physiopathological conditions, and are very well known to play vital roles in conditions such as stroke, autism, diabetes, gastrointestinal diseases, and pain transmission, among others.
Therefore, the bulk of the drugs that target peptide receptors have always relied on this peptide category as a means of improving both the deliverability, as well as the efficacy of such drugs. Also, it is worth pointing out that there are various pharmacological compounds with the ability to control the production, as well as the breakdown of these kinds of peptides – regulatory peptides.
Several such peptides are also under clinical trials for use in vaccines, sweeteners, food additives, cosmetics, and antibiotics.
Consequently, biologically active regulatory peptides are viewed as versatile compounds that can be applied in a wide variety of spectrums within the research field, including applications in chemistry, biology, physiology, and pharmacology where they have been viewed as strong prospects for the potential development of novel therapeutic drugs.
Most of the regulatory peptides are known to apply their biological effects through GPCRs – G-protein coupled receptors. This is not surprising in any way, given that they have always been the target of a variety of drugs that currently deploy the deliverability, as well as the efficacy of regulatory peptides. Compounds that work through GPCRs have been proven to have the ability to activate downstream signaling pathways.
This ability of functional selectivity, as displayed by regulatory peptides, is often referred to as biased signaling. For example, the dopamine D2 receptor is one pharmacological compound that has already displayed functional selectivity. Some of its notable practical applications have been in pain relief, as well as the treatment of a variety of psychiatric disorders.
One of the largest families of regulatory peptides, is neuropeptides. These peptides are regulatory peptides responsible for regulating a variety of physiological functions within the central nervous system and the peripheral organs. For example, the corticotropin-releasing factor is a perfect example of a neuropeptide, whose responsibility is to initiate the hormonal response to stress. It does this through the stimulation of the pituitary adrenocortical axis, as well as the sympathetic system. Corticotropin-releasing factor – CRF, also has the ability to act as a neuromodulator within the brain, where it can stimulate certain stress-related behaviors.
In a study conducted by Stengel and Tache, a comprehensive review of various mechanisms that affect how somatostatin signaling is able to suppress the CRF receptor-mediated response to stress, was done. Somatostatin acts within the pituitary glands where it reduces the secretion of CRF-induced corticotropin.
Also, somatostatin may act centrally to stop or delay the stress-induced activation of the sympathetic system. It does this by attenuating the stress response that is normally occasioned by food restrictions. The hormone can also counteract the actions of CRF on the gastrointestinal motor functions. Due to all these properties, certain somatostatin receptors are currently being considered for use in preclinical studies where they are being used to selectively modulate some of the various components associated with stress responses.
The sensory neurons responsible for producing somatostatin, have been discovered to have a non-selective cation channel TRPA1 – which is part of the transient receptor potential of the Ankyrin channel group. The functions of TRPA1 can be regulated by inorganic dimethyl trisulfide – DMTS and sodium polysulfide – POLY. The effects of both DMTS and POLY on sensory neurons present in carrageenan-evoked hind paw inflammation, has been extensively studied and compared. One such study involved the use of genetically modified mice that didn’t have TRPA1. During the study, it was observed that somatostatin when combined with sst4 could become an important mediator in the functions of DMTS, as well as the functions of POLY.
Certain studies have also shown that there is strong evidence to suggest that neuropeptide Y, also known as NPY, has the ability to attenuate stress responses autonomic regulations, fear, and anxiety. One of the studies revealed that when Y1R-preferring receptors agonist was administered intranasal, it could hinder stress-induced depressive behaviors. It could also hinder some of the effects of single prolonged stress on CRF mRNA expression. The importance of these differential effects of NPY and its Y1R-preferring agonists on GR and CRF expression still need further studies to help in defining and understanding the clear pathways through which the agonists are able to elicit such reactions.
Various neuropeptides play a variety of roles when it comes to the regulation of the functions of glial cells. It should be noted that microglial cells are part of the cell groups responsible for immune surveillance, right within the central nervous system. In most cases, these cells are usually expressed in two types of bradykinin receptors - B2R and B1R. The roles of these receptors in microglial activation has been examined in a variety of studies.
During in vitro studies, B1R was found to have the ability to enhance the production of NO, as well as the release of the pro-inflammatory cytokine, known as TNF-alpha within the microglial cells. In a study involving transgenic Alzheimer’s disease mice, it was observed that when B1R was administered intranasal, there was rapid microglial accumulation within the vortex. This finding gave more credence to the view that B1R modulation can be investigated as a potential therapeutic strategy for treating or managing Alzheimer’s disease.
Both astroglial cells and neurons have been found to express hemoglobin (Hb). It has also been discovered that the transcription of the Hb gene is usually greatly improved during the preconditioning phase of ischemia. Studies that the Hb has certain properties, which give it the capability to exert a protective effect during situations of oxidative stress, as well as apoptosis in cultured rats. This glioprotective activity of Hb is believed to be enhanced through the help of PKC, MAK, and PKA signaling pathways. With the data obtained from these studies, it is strongly believed that Hb may have the ability to successfully cause neuroprotection during instances of neurodegenerative conditions or diseases.
Activity-dependent neuroprotective protein – ADNP is one of the glioproteins responsible for mediating the neuroprotective activities of the VIP – vasoactive intestinal peptide. Mutations involving this peptide have been observed in patients suffering from neurodegenerative conditions such as autism. In one of the reports describing a clinical phenotype of a 10-year old girl with an ADNP mutation, it was observed that the girl showed signs of craniofacial asymmetry, motor skill deficiency, difficulty in talking, and global developmental delay. The report also suggested that a short bioactive peptide fragment of ADNP could be used as a potential therapeutic option for dealing with conditions such as ADNP mutations, also known as Helmoortel-Van der Aa syndrome.
There are various hormones present in the gastrointestinal tract whose responsibility is to control energy homeostasis and appetite. However, very little is known about them when it comes to their interactions with different kinds of hormones. In a study conducted to investigate the effects of ghrelin on glucagon-like peptide known as GLP-1 and insulin secretion in mice, it was observed that intravenous application of ghrelin had the potential of causing a significant increase in the release of plasma GLP-1 when a glucose intolerance test was done. However, the application did not have any effects on the circulation of the levels of glucose, insulin, and GIP. In the in vitro studies, it was observed that ghrelin could inhibit the expression of proglucagon mRNA within the glutag cell lining. The data from the study indicated that ghrelin may have opposite effects on GLP-1 gene transcription and secretion.
Apart from their applications as nutriments, food-derived regulatory peptides may also have the ability to portray multiple regulatory actions. Specifically, protein digestion-derived peptides are believed to have the ability to control appetite by simply modulating the secretion of the gut hormone. It is also believed that alimentary peptides may impact the activities of ubiquitous enzyme DPP-IV. This is the enzyme that is responsible for inactivating the actions of GIP, as well as GLP. It usually achieves this by trimming off their N-node residues.
Also, peptides obtained from food proteins may sometimes function as agonists of peripheral opioid receptors. When the opioid receptors are activated, they can stop gastric emptying, which may in turn lead to food intake-induced satiety. Food protein peptides, therefore, have the potential of producing a plethora of regulatory peptides that may end up helping to control glucose homeostasis and food intake.
At this point, it is worth pointing out that there are several peptides that are heavily involved with regulating the proliferation and migration of tumor cells. More specifically, VIP has been proven to inhibit the proliferation, as well as the migration of small cell lung carcinoma. Because it is possible to express VIP receptors in bladder carcinoma, studies suggest that intramuscular application of bladder cancer cells may lead to a high mortality rate in VIP-KO mice, when compared to wild mice. In vitro, VIP was found to slow down and inhibit the growth of cultured MB4 cells – the cells responsible for causing bladder cancer. From this study, it was suggested that VIP had an immense therapeutic value, which could be tapped in designing treatments and therapies for dealing with bladder carcinoma.
Neuromedin B, bombesin, and gastrin-releasing peptide are mammalian peptides that have showed a lot of therapeutic potential when it comes to the formulation of cancer therapies. These peptides all function through three types of GPCRs with designations of BB1R, BB2R, and BRs-3. There are various types of cancer cells that have been shown to express neuromedin B and GRP, as well as their receptors. These peptides and their receptors function as autocrine factors, where they help in stimulating the growth of the tumors. Gastrin is normally produced in the stomach where its function is to stimulate the secretion of gastric acid. The peptide is also produced by a variety of malignant cancer cells, known as gastrinomas. In a literature review involving the role of gastrin in the etiology of gastric cancer, it was possible to pinpoint the main role of gastrin in gastric carcinogenesis. With the results, gastrin antagonists could be used as a prophylaxis for conditions such as gastric cancer.
There is enough evidence to suggest that GPCRs play a significant role in the various tumorigenesis processes, including the survival, migration, and proliferation of cancer cells. Various hormones with the ability to act through GPRCs have also been determined to play a vital role in the progression, as well as metastasis of ovarian cancer. In a literature review by Zhang et al, regarding the role of estrogen luteinizing hormone, follicle-stimulating hormone, and thyroid-stimulating hormone in ovarian tumorigenesis, it was observed that hormones acted as chemotherapy agents that countered the development of ovarian tumor cells, suggesting that they could be beneficial to patients suffering from ovarian neoplasm.
Based on the above, it is abundantly clear that regulatory peptides have a variety of functions affecting the body’s physiological systems. One area that has been of great concern to researchers, is the multiple functions of the regulatory peptides on the cardiovascular system. More specifically, the vasoactive peptide known as apelin, has been proven to enhance the ability of the cardiac muscles to contract, as well as increase the release of vasodilators. The apelin peptide has a short lifespan of only five minutes, and though short-lived, its effects on hydromineral balance, as well as activities such as a peripheral and central agonist on the cardiorenal functions has been promising, making it a potential candidate for the development of therapies for a variety of cardiovascular conditions.
- Chrousos GP, Zoumakis E. Milestones in CRH research. Curr Mol Pharmacol (2017) 10:259–63. doi:10.2174/1874467210666170109165219
- Wu G, Feder A, Wegener G, Bailey C, Saxena S, Charney D, et al. Central functions of neuropeptide Y in mood and anxiety disorders. Expert Opin Ther Targets (2011) 15:1317–31. doi:10.1517/14728222.2011.628314
- Fleisher-Berkovich S, Filipovich-Rimon T, Ben-Shmuel S, Hülsmann C, Kummer MP, Heneka MT. Distinct modulation of microglial amyloid β phagocytosis and migration by neuropeptides (i). J Neuroinflammation (2010) 7:61. doi:10.1186/1742-2094-7-61
- Biagioli M, Pinto M, Cesselli D, Zaninello M, Lazarevic D, Roncaglia P, et al. Unexpected expression of alpha- and beta-globin in mesencephalic dopaminergic neurons and glial cells. Proc Natl Acad Sci U S A (2009) 106:15454–9. doi:10.1073/pnas.0813216106
- He Y, Hua Y, Liu W, Hu H, Keep RF, Xi G. Effects of cerebral ischemia on neuronal hemoglobin. J Cereb Blood Flow Metab (2009) 29:596–605. doi:10.1038/jcbfm.2008.145
- Larsen E, Menashe I, Ziats MN, Pereanu W, Packer A, Banerjee-Basu S. A systematic variant annotation approach for ranking genes associated with autism spectrum disorders. Mol Autism (2016) 7:44. doi:10.1186/s13229-016-0103-y
- Rehfeld JF, Larsson LI, Goltermann NR, Schwartz TW, Holst JJ, Jensen SL, et al. Neural regulation of pancreatic hormone secretion by the C-terminal tetrapeptide of CCK. Nature (1980) 284:33–8. doi:10.1038/284033a0
- Tan T, Bloom S. Gut hormones as therapeutic agents in treatment of diabetes and obesity. Curr Opin Pharmacol (2013) 13:996–1001. doi:10.1016/j.coph.2013.09.005
- Horner K, Drummond E, Brennan L. Bioavailability of milk protein-derived bioactive peptides: a glycaemic management perspective. Nutr Res Rev (2016) 29:91–101. doi:10.1017/S0954422416000032