GPCR signaling and its importance as a pharmacological target

 Introduction

There are several important concepts in biochemistry that explain how certain things work in our bodies. Of these, cellular communication is a crucial topic to discuss. Through the elegance of this complex process, our body is able to establish communication routes to produce a desired outcome. Have you ever wondered how you know you are hungry? Or how do your hands quickly move away if you accidentally touch something extremely hot? Your body has its own USPS system that serves to establish communication channels to respond to various environmental stimuli. 

One such important cellular communication platform is the GPCR signaling or the G-protein coupled receptors. These receptors are highly expressed in the human genome and are responsible for signal transduction in various metabolic pathways. 1 Hence, serving as a major pharmacological target to treat numerous metabolic diseases. 

In this blog, I am going to discuss the basics of GPCRs mediated signal transduction and how they can be pharmacological targets for treating metabolic diseases like type 2 diabetes and obesity. I hope after reading this blog, you appreciate the complexity of GPCR-mediated signal transduction and how this protein family is a very important aspect your body treasures. 

What is GPCR signaling?

When our body receives a signal (or described as an environmental stimulus), it will amplify this signal through secondary messengers or phosphorylation*. Signal amplification triggers a required response within a target cell. 

So where do GPCRs matter? They are a transmembrane family of proteins that have a signal binding site on the extracellular side and G-proteins on the intracellular (or cytosolic side) of the receptor. That is why they are referred to as G-protein-associated receptors. G-proteins are heterotrimeric meaning they have 3 protein subunits: Gα𝛃ᵞ. Gα when inactive is associated with G𝛃ᵞ. Gα is inactive when associated with GDP. When a signal binds to the extracellular side of GPCR, a conformational change causes GDP-GTP exchange. GTP bound Gα is now active and this causes its dissociation from G𝛃ᵞ. While Gα is still associated with the plasma membrane, it binds to the enzyme called adenylyl cyclase that produces cAMP, a secondary messenger molecule, from ATP. cAMP later binds to the regulatory subunit of the phosphorylating A (PKA) enzyme. This causes PKA activation which leads to the phosphorylation of downstream effectors, causing the desired effect. Please refer to figures 1a and 1b for a graphical representation of GPCR-mediated signal amplification. 

Figure 1a. Steps required for activating GPCR signaling pathway2 

Figure 1b. Downstream effects of GPCR signaling pathway3

Importance in diabetes treatment 

In a healthy person, when the body senses the external stimuli of high blood glucose levels, insulin from pancreatic islets is produced. The produced insulin is useful for storing glucose for long-term energy purposes. The pancreatic islets have insulin-producing beta cells that enable this response. However, in type 2 diabetes, an increased level of blood glucose does not trigger insulin production. This causes beta-cell dysfunction that ultimately leads to high blood glucose levels. Unfortunately, type 2 diabetes is a ubiquitous disease due to the modern lifestyle that encourages high sugar diet and minimal exercise. 

Pharmaceutical companies have targeted a GPCR signaling pathway to help treat diabetes. Novel anti-diabetic medicines target GLP-1R, a GPCR responsible for insulin secretion. Targeting this GLP-1R leads to increased levels of cAMP that ultimately cause the production of insulin.4 

This kind of targeting is specific to insulin secretion that will be a useful treatment for diabetes. Pharmacological research tends to aim for such signaling pathways to elicit a specific response. If a pathway responsible for multiple functions is targeted, there are chances that those functions are altered. This might cause other undesired side effects. Therefore, finding such specific targets is essential for drug development. 

Importance in obesity treatment 

Another example of such a potential pharmacological target can be useful for treating obesity, another manifestation of unhealthy patterns associated with modern lifestyle. Obesity is a result of an energy imbalance that promotes high energy input and lower energy output. It is important to treat obesity as it is linked with cardiovascular and other metabolic diseases. 

A potential treatment for obesity involves targeting the Melanocortin 4 receptor, a highly conserved GPCR expressed in CNS, especially in the paraventricular nucleus of the hypothalamus (PVN). PVN receives signals from ARC (arcuate nucleus of the hypothalamus) that release catabolic proopiomelanocortin-expressing neurons (POMC) and anabolic agouti-related peptide-expressing neurons (AgRP). ARCPOMC releases MC4R agonist** alpha-melanocyte-stimulating hormone that causes reduced food intake and increased energy expenditure. ARCAgRP releases an inverse agonist*** for MC4R that promotes energy uptake. MC4R mutations represent prevalent monogenic obesity. Loss of function MC4R mutations linked with an early onset of obesity due to hyperphagia and reduced energy expenditure.5

So perhaps targeting ARCPOMC can induce the feeling of satiety and limit energy intake. Thus, pharmacological targets like these can help us treat or reduce the effects of intaking high-caloric foods. 

Conclusion

After reading this blog about GPCRs, I hope I have invoked a feeling of gratitude toward this amazing protein family. Its presence in our genomes has enabled complex communication pathways that establish metabolic routes. It is crucial to study GPCRs as they are important pharmacological targets for treating various metabolic diseases. With that being said, I will meet you all next time with another biochem blog. Until then, take care!

Footnotes

* phosphorylation is a method of protein modification where a phosphate group is added to a protein, hence, activating it

** agonist is a molecule that binds and activates a target receptor

*** inverse agonist is a molecule that binds a receptor but does not activate it. It antagonizes an agonist. 

Works cited

1. Schöneberg, T., & Liebscher, I. (2020). Mutations in G Protein–Coupled Receptors: Mechanisms, Pathophysiology and Potential Therapeutic Approaches. Pharmacological Reviews, 73(1), 89–119. https://doi.org/10.1124/pharmrev.120.000011

2. ‌Khan Academy. (2023). Khanacademy.org. https://www.khanacademy.org/science/ap-biology/cell-communication-and-cell-cycle/signal-transduction/a/signal-perception

3. G-protein signaling. (2018). https://www.cisbio.com/dd/by-universe/g-protein-signaling

4. Barella, L. F., Jain, S., Kimura, T., & Pydi, S. P. (2021). Metabolic roles of G protein‐coupled receptor signaling in obesity and type 2 diabetes. The FEBS Journal, 288(8), 2622–2644. https://doi.org/10.1111/febs.15800

5. Deng, Y., Deng, G., Grobe, J. L., & Cui, H. (2021). Hypothalamic GPCR Signaling Pathways in Cardiometabolic Control. Frontiers in Physiology, 12. https://doi.org/10.3389/fphys.2021.691226