What makes G-protein coupled receptors (GPCRs) highly desirable drug targets?

By Nishka Mahajan

G-protein coupled receptors (GPCRs) comprise the most extensive class of cell-surface receptors within eukaryotes, with over 820 encoded by the human genome. They are primarily responsible for mediating multiple cell-signalling pathways (physiological processes), making them ideal targets for more than one-third of pharmaceutical applications and therapeutic interventions. Furthermore, their characteristic features of being present on cell surfaces, possessing regulatory allosteric binding sites and suitability for computer simulations/screening make it relatively easy to design an effective drug.1

GPCRs are unique membrane receptors. Each receptor constitutes a lengthy protein with three fundamental sections: an intracellular part (termed the C-terminus), an extracellular part (termed the N-terminus), and a middle portion including seven transmembrane alpha-helices. The initiation process involves the binding of an extracellular signal molecule (ligand) to a GPCR (orthosteric site), triggering the seven transmembrane alpha-helices to undergo a conformational change. This change then activates the C-terminus, which in turn directs a substance to activate the G-protein (specialised heterotrimeric proteins possessing the ability to bind GTP/GDP). Consequently, the G-protein associates the corresponding receptor to the respective ion channels or enzymes present in the cell membrane.2Different ligands induce distinct receptor conformations, and each conformational state initiates a unique downstream signal. Pharmaceuticals can use this finding as an opportunity to specifically obstruct pathologically involved pathways while leaving regular homeostatic processes undamaged.3 To maximise safety and efficacy, the best approach would be to deliver a proven therapeutic agent with a targeting ligand that displays less affinity for healthy cells but a high affinity for pathologic cells.4 A recent research study corroborates the notion of using various biological mechanisms to suppress tumour growth such as peptides that bind to tumour-specific cell-surface receptors, therapeutic agents such as apoptotic peptides, suicide genes, imaging dyes or chemotherapeutics; all while avoiding causing any harm to the healthy cells.5

G-proteins are attached to the cell membrane by lipid anchors. They are of various types – each specific for corresponding GPCRs and distinct target proteins. Further, composed of three different protein subunits, namely α, β, and γ. In unstimulated conditions, when the G-protein is inactive, the α subunit binds a GDP molecule. When the GPCR is activated, it influences the α subunit to exchange its bound GDP for GTP. This change in binding leads to a conformational change, freeing the G protein from the GPCR and activating the dissociation of the α subunit from the β and γ subunits. Now, these (α subunit and the β-γ-dimer) associate with numerous potential targets, for example, ion channels and enzymes in the plasma membrane, which forward the signal along.2

Certain G-proteins are also responsible for regulating the production of cyclic AMP (cAMP). cAMP behaves like a secondary messenger in several signalling pathways. It is synthesized using ATP by an enzyme known as adenylyl cyclase – a transmembrane protein with its interactive region facing the cytosolic side of the plasma membrane. The activated αs subunit of Gs protein stimulates the enzyme to convert ATPs into cAMPs. Consequently, the concentration of cAMP increases in the cell, activating cAMP-dependent protein kinase A (PKA). PKA further phosphorylates different transport proteins, metabolic enzymes, transcription factors or structural proteins – modulating their activity, incidentally affecting various cellular functions. For example, myocardial cells contain a β-1 receptor (Gs protein-coupled receptor) which is stimulated by adrenaline (ligand), activating the adenylyl cyclase pathway. This eventually leads to the phosphorylation of proteins that sequester calcium into the sarcoplasmic reticulum, ultimately causing an increase in the contractility of cardiac myocytes. Alternatively, the activated αi subunit of Gi protein inhibits adenylyl cyclase – processes occurring at the baseline rate stop, ultimately reducing the activity of the cell. The SA node contains the M2 receptor (Gi protein-coupled receptor) which is activated by acetylcholine (ligand), inhibiting the activity of adenylyl cyclase. As a result, impulse generation decreases, and the heart rate falls.2

Owing to their regulatory behaviour, Gs and Gi make essential targets for medically significant bacterial toxins. Cholera toxin, produced by a bacterium responsible for causing cholera, is a catalytic enzyme for the reaction involving the transfer of ADP ribose from intracellular NAD+ to the αs subunit of Gs protein. This process of ADP ribosylation permanently alters the αs subunit, making it no longer possible for it to hydrolyse its bound GTP. Therefore, it remains activated and stimulates adenylyl cyclase indefinitely. This results in an elevated concentration of cAMP within intestine’s epithelial cells, leading to a major efflux of chloride ions and water into the gut and inducing severe diarrhoea that indicates cholera. Pertussis toxin, which is produced by a bacterium responsible for causing whooping cough (pertussis), catalyses the ADP ribosylation of the αi subunit of Gi protein. This prevents the protein’s association with receptors; therefore, the Gi protein remains inactive and bound to a GDP molecule, being unable to perform its function of regulating target proteins. Because of this, Cholera and Pertussis toxins are conventionally used in scientific experiments to understand if a cell’s response to a signal involves mediation by Gi or Gs.2

Several GPCRs also perform their function by activating the inositol phospholipid signalling pathway. This involves using Gq proteins that activate phospholipase C-β (PLCβ), an enzyme present bound to the plasma membrane. PLCβ acts on phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], cleaving it to generate two products: inositol 1,4,5-trisphosphate (IP3) and diacylglycerol. IP3 leaves the plasma membrane, is free to roam and diffuses rapidly through the cytosol. On reaching the endoplasmic reticulum, it activates calcium channels releasing Ca2+ in the cytosol used for various purposes. On the other hand, diacylglycerol has hydrophobic tails that keep it anchored to the plasma membrane. Here, it behaves as a secondary messenger, its major functions include activating protein kinase C (PKC), which further phosphorylates target proteins and the signal process is perpetuated.2

The αq subunit, as a protein, has various functions that are of therapeutic importance. Its key GTPase activity, wherein it exchanges bound GDP for GTP, forms an ideal drug target. A research study explores the same theory. YM-254890, a cyclic depsipeptide separated from Chromobacterium sp., prevents the exchange of GDP for GTP and therefore inhibits Gαq signalling pathways.6 When YM-254890 was used in a rat model of carotid artery thrombosis, it displayed anti-platelet aggregation, antithrombotic, and thrombolytic properties. Therefore, it can be concluded that compounds possessing the ability to inhibit Gαq could exhibit massive potential in treating thrombotic conditions within humans, for instance, thrombotic stroke or myocardial infarction. Furthermore, several studies also implicate that Gαq protein plays a role in varied metabolic conditions such as obesity and type 2 diabetes.7, 8 On activation, Gαq causes an increase in blood glucose levels within a mouse model, therefore, if a compound inhibits Gαq it could consequently be used as a prospective treatment alternative for type 2 diabetes.

In recent years, there have been massive advances in disease-relevant research on G-protein coupled receptors. Scientists and researchers strategize to target GPCRs therapeutically by comprehending the mechanism of a ligand to activate a respective GPCR triggering a signalling cascade. The methods involved include pharmacological tools – biochemical/physiological techniques, X-ray crystallography and computational methods that ultimately elevate research to greater potential.


  1. Edward Zhou X, Melcher K, Eric Xu H. Structural biology of G protein-coupled receptor signaling complexes. Protein science: a publication of the Protein Society. 2019;28(3): 487–501. https://doi.org/10.1002/pro.3526.
  2. Alberts, B. Molecular Biology of the Cell. 6th edition, CRC Press; 2017. https://bibliu.com/app/#/view/books/9781317563747/epub/ops/xhtml/toc.html.
  3. Bologna Z, Teoh JP, Bayoumi AS, Tang Y, and Kim IM. Biased G protein-coupled receptor signaling: new player in modulating physiology and pathology. Biomolecules & Therapeutics. 2017;25: 12–25. doi: 10.4062/biomolther.2016.165.
  4. Srinivasarao M, Low PS. Ligand-Targeted Drug Delivery. Chemical reviews. 2017;117(19): 12133–12164. https://doi.org/10.1021/acs.chemrev.7b00013.
  5. Yao VJ, D’Angelo S, Butler KS, Theron C, Smith TL, Marchiò S, Gelovani JG, Sidman RL, Dobroff AS, Brinker CJ, Bradbury A, Arap W, Pasqualini R. Ligand-targeted theranostic nanomedicines against cancer. Journal of controlled release: official journal of the Controlled Release Society. 2016;240: 267–286. https://doi.org/10.1016/j.jconrel.2016.01.002.
  6. Kamato D, Thach L, Bernard R, Chan V, Zheng W, Kaur H, Margaret B, Osman N, Little PJ. Structure, Function, Pharmacology, and Therapeutic Potential of the G Protein, Gα/q,11. Frontiers in Cardiovascular Medicine. 2015;2: 2297-055X. https://www.frontiersin.org/article/10.3389/fcvm.2015.00014.
  7. Li JH, Jain S, McMillin SM, Cui Y, Gautam D, Sakamoto W. A novel experimental strategy to assess the metabolic effects of selective activation of a G(q)- coupled receptor in hepatocytes in vivo. Endocrinology. 2013;154: 3539–3551. doi:10.1210/en.2012- 2127.
  8. Kimple ME, Neuman JC, Linnemann AK, Casey PJ. Inhibitory G proteins and their receptors: emerging therapeutic targets for obesity and diabetes. Experimental & Molecular Medicine. 2014;46: e102. doi:10.1038/emm.2014.40.
  9. Basith S, Cui M, Macalino S, Park J, Clavio N, Kang S, Choi S. Exploring G Protein-Coupled Receptors (GPCRs) Ligand Space via Cheminformatics Approaches: Impact on Rational Drug Design. Frontiers in Pharmacology. 2018;9: 1663-9812. https://www.frontiersin.org/article/10.3389/fphar.2018.00128.

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