G-Protein Coupled Receptors of The Renin-Angiotensin System Assignment Sample

• Subject Name : Biology

Commentary Essay

The G protein-coupled receptors (GPCR) are proteins found in the cell membrane that hold together the extracellular substances so that signals can be transmitted from them to an intracellular molecule called guanine nucleotide-binding protein or G protein. GPCRs influence one’s senses involving vision, pain, smell, and taste. They are also a part of the cell recognition and communication process, making them favourable targets for drug development procedures.

The location of the GPCR within the cell, along with its function is what attributes to its medical relevance. The positioning of the GPCR covers the plasma membrane within the cell, connects the intracellular and extracellular regions and provides a direct pathway between the intracellular responses to the messages from the extracellular environment. Some of the common functions of these receptors are – monitoring firing of the neurons, regulating the transportation of ions through the plasma, maintaining homeostasis, controlling cell division and changes in cell morphology. A disturbance in these functions can result in the occurrence of serious illnesses.

A study conducted by McMahon et al. (2020) explains the development of a methodology to overcome the challenges brought about using GPCRs as targets and finding functionally modulatory antibodies in the process. It is difficult to conduct antibody discovery methods on the GPCRs on account of their biochemical instability after purification and is highly conserved across species. The methodology used in this study involved a yeast surface display of antibody fragments of synthetic camelid, known as nanobodies. Multiple nanobodies have been known to fight against angiotensin II type 1 receptor. These fragments were then placed inside the bodies of mice to show that they can be used to modulate blood pressure.

After the infusion, a matured nanobody with comparable antihypertensive properties to angiotensin receptive blocker losartan was developed. Through this study, we understand the importance of antibody approaches in treating conditions where it is not possible to develop small molecule drugs. It also provides insight on the procedure by which nanobody contenders can treat hypertensive disorders in situations where small molecule drugs targeting the angiotensin II type 1 receptor are refuted.

Angiotensin II has been used to regulate renal and cardiovascular homeostasis and overstimulation of this can disrupt this balancing, causing illnesses.GPCRs when activated, can initiate different forms of signals that aid in regulating various physiological processes, which include regulation of blood pressure. This is essential for the normal functioning of the cardiovascular system.

The most significant regulator of blood pressure in the human physiology, known as the renin-angiotensin system or RAS distributes three different types of GCPRs – angiotensin type-1, angiotensin type-2 and MAS1 receptors. Maintaining normal blood pressure is a function of the angiotensin type 1 receptor and high levels of it cause hypertension. Extremely high or low levels of salt trigger renal processes, activates the angiotensin type 1 signals, resulting in hypertension and ending organ damage.

There are regulatory mechanisms that are subjected to GPCR control. The GPCR affects constriction and relaxation and blood vessels, increases protein and DNA synthesis and indirectly regulates the RAS tissues. Since the significance of the contributions of GPCR is quite clear, it is essential to further explore their relation to the mechanisms associated with changes in blood pressure and formulate GPCR targeted interventions and medical modalities (Jara et al., 2019).

G protein-coupled receptors comprise of the largest receptor family in the human genome. They consist of around 800 members. Their importance lies in the roles of signalling responses to various extracellular stimuli, from hormones and proteins to neurotransmitters., Given their involvement in various physiological phenomena, it is considered essential that they aretargeted during drug development.

Progress has been made in the understanding of details pertaining to ligand binding and signalling by studying the GCPR crystallography (Maeda et al., 2018). However, despite advancements in technology, it has been difficult to extract quality fragments from the GCPR crystallography, due to the requirement of drastic protein engineering. Since antibodies bind to their specific targets, protein engineering is also required to structurally alter antibodies and allow structural determination of the GPCRs.

Evidence suggests that components of the renin-angiotensin system, namely AngIIand Ang1-7, are harmful and protective against cancer respectively. Developing substances that target each of the RAS receptors may prove to be an effective technique against cancer. Since angiotensin peptides are known to bind with GPCRs thereby activating them, these angiotensin GPCRs can be declared as potential therapeutic targets.

The GPCRs are exposed at the cell surface, making them easy to target with medicinal drugs or humanized blocking antibodies. Angiotensin Receptor Blockers are already being used to treat hypertension, perhaps their use can be extended to help with conditions such as breast cancer, along with other standard procedures. This approach of using angiotensin receptor blockers along with other procedures such as chemotherapy may end up becoming promising. Angiotensin receptor blockers have been shown to reduce the toxicity of chemotherapy using anthracycline, while Ang1-7 has reduced cytopenia of patients diagnosed with ovarian cancer receiving chemotherapy based on gemcitabine. Hence, the use of angiotensin receptor blockers and Ang1-7 together with chemotherapy would help increase the efficiency of treatment and reduce instances of side-effects (Rodrigues-Ferreira& Nahmias, 2015).

From the pieces of evidence stated above, it is clear that by conducting further research on the functioning of G protein-coupled receptors, novel drugs can be developed to manage an array of diseases. Their unique recognition mode creates a possibility to transfer its properties to the other G-protein subtypes through minimal protein engineering. Liganded GPCRs along with other prototypes of GPCR rhodopsin, provide insights into the structure and function of the biochemical processes of the GPCR family, which will ultimately lead to the development of new interventions and pharmacological strategies. It is because of their medical relevance that they are the preferred targets during drug development.

Mutations in GPCRs can result in a plethora of serious illnesses such as hormonal imbalances, issues related to fertility, diabetes and obesity. Further research exploring their medical relevance with respect to chronic and incurable illnesses should be encouraged and conducted further so that the medical world can benefit. Medicines and drugs developed based on the results of this research can help tackle a wide variety of issues.

References for G-Protein Coupled Receptors of The Renin-Angiotensin System

Jara, Z. P., Singh, K. D., Unal, H., Desnoyer, R., Yokota, R., Pesquero, J. L., ... &Karnik, S. S. (2019). Effect of novel GPCR ligands on blood pressure and vascular homeostasis. In Methods in cell biology (Vol. 149, pp. 215-238). Academic Press.https://doi.org/10.1016/bs.mcb.2018.10.001

Maeda, S., Qu, Q., Robertson, M. J., Skiniotis, G., &Kobilka, B. K. (2019). Structures of the M1 and M2 muscarinic acetylcholine receptor/G-protein complexes. Science, 364(6440), 552–557. https://doi.org/10.1126/science.aaw5188

McMahon, C., Staus, D. P., Wingler, L. M., Wang, J., Skiba, M. A., Elgeti, M., Hubbell, W. L., Rockman, H. A., Kruse, A. C., & Lefkowitz, R. J. (2020). Synthetic nanobodies as angiotensin receptor blockers. Proceedings of the National Academy of Sciences, 117(33), 20284–20291. https://doi.org/10.1073/pnas.2009029117

Rodrigues-Ferreira, S., & Nahmias, C. (2015). G-protein coupled receptors of the renin-angiotensin system: new targets against breast cancer? Frontiers in Pharmacology, 6, 24. https://doi.org/10.3389/fphar.2015.00024

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