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G-Protein Coupled Receptors

Paper Type: Free Essay Subject: Sciences
Wordcount: 3889 words Published: 23rd Sep 2019

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G-Protein Coupled Receptors


 G-protein coupled receptors are the most diverse and largest of the membrane receptors in eukaryotes. (1) These are known as cell surface receptors, which act as an inbox for messages in the form of peptides, sugars, energy, lipids and proteins. (1) These messengers inform cells about the present/absence of light or life-sustaining proteins in their environment. GPCR’s are known for conveying information sent by others and take part in a lot of important roles in the human body. “It is estimated by research that between one-half of all marketed drugs act by binding to GPCRs.” (2) In the human body there are hundreds of different types of GPCR and a diverse type of ligand which bind to these receptors. The receptors might be odor molecules, neurotransmitters, peptide hormones or others. All these structures have a similarity, which is its seven transmembrane domains structure. (2) The purpose of GPCR is to couple the binding of agonists to the activation of specific heterotrimeric G proteins, leading to the modulation of downstream effector proteins. GPCR can also be found in yeast, choanoflagellates and other animals. (3)

History of the discovery of protein:

 Studying GPCR’s in their crystalized state was difficult due to the limited amount of technology present, this was immensely challenging for all the scientist. For crystallographer’s, membrane proteins have always been a nuisance and GPCR’s were especially defiant. In the 90’s there were a series of breakthroughs which allowed the detailed structural characterization of GPCR. (4) The beta-adrenergic receptor (BAR) was a model organism of the GPCR, which was bounded to adrenaline. This brought about the “fight-or-flight” response among other things. Robert Lefkowitz, in the 80’s introduced “the modern study of GPCRs by first cloning and sequencing the genes for the BARs.” (4)  This study of Robert Lefkowitz stated that all the genes were similar to those for rhodopsin’s (GPCRs which sense light). This study resulted in a common structure for all GPCR’s. Arrestins was first identified by Lefkowitz, which were responsible for GPCR deregulation and control. (4) Robert Lefkowitz could be called the ‘father of modern GPCR research’ due to his vital research on GPCR’s which helped people understand more about these proteins. “Krzysztof Palczewski in the 2000’s became the first person to obtain crystals of rhodopsin.” This was a major breakthrough as there was a lot of speculation about the structure but not enough evidence. The crystals were low resolution and couldn’t shed a light on the details of GPCR activation. The project was passed onto Kobilka’s group, who was a postdoc to Robert Lefkowitz. (4) In 2007, Kobilka’s group focused mainly on the structure of the GPCR. With the help of crystallography, they achieve the impossible. There are many paths for crystallizing a particular protein and requires manipulation, trial and error and sheer persistence to achieve the desired result. The combination which lead to the crystal structure was, “an antibody which stabilized the GPCR when it was lifted out of the membrane.” (4) Then a bacteriophage virus was used to stabilize the second structure. Another breakthrough came when an active state of GPCR was crystalized as it was previously thought to be too unstable to be isolated. The comparison between the active and inactive state shed a light to how a GPCR functions and how the G-protein binding process happens. (4) “In 2011, Kobilka’s group published the coup-de-grace, which had the first ever structure of a GPCR bound to a G protein.” (4) Due to these contribution’s the belief that GPCR can’t be crystalized, had been debunked. In the last 10 years dozens of crystalized structures of GPCR’s have been resolved, such as dopamine receptor, he adenosine A2 receptor and the CXCR4 chemokine receptor. There is still a lot we don’t know about GPCR’s, so as technology advances we will have better methods/techniques to understand more about these fascinating proteins. (4)

Mechanism of function:

 External signals such as ligand binding or other signal mediators activate the G protein-coupled receptors, which creates a conformational change in the receptor. This results in the activates the G-protein. The different types of mechanisms are;

  1. Ligand Binding

When an antagonist binds to a GPCR’s receptor, it activates the GPCR. The binding leads to a conformational change of the receptor, this causes “a disruption of a strong ionic interaction between the third and sixth transmembrane helices.” (9) This activates the G-protein heterotrimer. (9)

  1. Conformational change

“In an inactive state the transduction of the signal through the membrane by a receptor is still not completely understood.” (9) The GPCR binds to the heterotrimeric G protein complex, making it inactive. (9) When an agonist binds to the GPCR, it causes a conformational change in the receptor. “The conformational change is then transmitted to the bound Gα subunit of the heterotrimeric G protein via protein domain dynamics. The GTP is converted to GDP with the help of the activated Gα subunit, this triggers the dissociation of Gα subunit from the Gβγ dimer and from the receptor.” (9) Other intracellular proteins interact with the dissociated Gα and Gβγ subunits to continue the signal transduction cascade. Now, another heterotrimeric G protein binds to a now free GPCR to form a new complex. (9)

  1. G-protein activation/deactivation cycle

The inactive α-subunit of a heterotrimeric G-protein is bound to the GEF domain, when the receptor is inactive. When GDP is reversibly bound to G-proteins its in an inactive state but when GTP is attached to the G-proteins its in its active state. (9) “Upon receptor activation, the GEF domain, in turn, allosterically activates the G-protein by facilitating the exchange of a molecule of GDP for GTP at the G-protein’s α-subunit.” (9) The dissociation of GDP at this point from the receptor leads to a yield of a Gα-GTP monomer and a tightly interacting Gβγ dimer. These are now free to modulate the activity of other intracellular proteins. (9)

  1. Cross-talk

Integrin signals, such as FAK interact with GPCRs downstream signals. The GPCR Gαs activity decreases as Integrin signaling phosphorylates FAK. (9)

  1. Hydrophobic interactions:

Water and hydrophobic interactions plays an important role between the interaction of drugs and its target. “When hydrophobic region of a drug interacts with a hydrophobic region of a binding site, water molecules added to a drug are freed and increase in entropy and binding energy takes place which is substantial.” (5) The amino acids valine, alanine, leucine, methionine, isoleucine, tryptophan, phenylalanine, proline, tyrosine, all have hydrophobic residues capable of interacting with each other by van der Waals interactions in rhodopsin. Hydrophobic residues come together due to the hydrophobic interactions and are very important. (5)


 Depending on the type of G-protein, different signalizing pathways can be activated. GPCR internalization attenuates signalling, which is caused by arrestin binding. Complex interactions of GPCRs with numerous intracellular proteins are regulated by Signalling, desensitization and eventual resensitization. (9) The primary sequence and tertiary structure of the GPCR limits the signalling pathways which are activated through a GPCR, but ultimately determined by the availability of transducer molecules and a particular conformation stabilized by a particular ligand. There are currently 2 types of transducers G-proteins and β-arrestins. (9) Due to β-arrestins having low affinity and to be phosphorylated form of most GPCRs, the majority of signalling is dependant on G-protein activation. (9) There are 2 types of signaling methods; The G-protein-dependent signaling and the G-protein-independent signaling. There are 3 main G -protein dependant signaling which are mediated by 4 sub classes of G-proteins, which are Gαs, Gαi/o, Gαq/11, and Gα12/13. (9) “Most GPCR are capable of activating more than one Gα-subtype, they also show a preference for one subtype over another. When the subtype activated depends on the ligand that is bound to the GPCR, this is called functional selectivity” (9) When an agonist binds it initiates activation of multiple different G-proteins, as a result it stabilizes more than 1 conformation of the GPCR’s GEF domain. On the other hand, G-protein-independent signaling are GPCR which may signal through G-protein-independent mechanisms. The heterotrimeric G-proteins may also play a functional role for the independent GPCRs. (9) “G-protein-dependent signaling such as β-arrs, GRKs, and Srcs may signal independently through many proteins. This signalling method is a relatively immature area of research.” (9) It contains GPCR-independent signaling by heterotrimeric G-proteins which acts as a signal transducer. There are currently 2 signal transduction pathways, the phosphatidylinositol signal pathway and the cAMP signal pathway. (9)

Current state of research about the protein:

 As mentioned before, the GPCR’s are very important and have 7-TM domains connected together by ICLs and ECLs. The following are the current state of research on GPCR. (8) How GCPR can affect the core of drug development can be achieved by understanding the following signaling methods:

  1. LiSS (Ligand-induced selective signaling),

The theory states that this signaling method causes change in pheonotic cell responses intermediated by intracellular ligand proteins initiated by agonist binding. The LiSS have two states an active and an inactive state. The active state allows the receptors to form many different forms and structures which therefore lead to highly selective specific ligand binding. This phenomenon is referred to as “functional selectivity” allowing specific drug development and reduced side effects associated with it. To understand more clearly the basis of selective ligand binding is due to the dynamic nature of the intracellular environment that changes the way the signaling is achieved. This allows targeted phenotypic responses for any pathophysiology leading to increased fixed benefits. An example is the GnRH I and GnRH II, operating on the same single GnRH type I receptor. Each has a specified role, one generates inositol phosphate the other has antiproliferative effects on certain cells. Even though both act on the same receptor the signaling effects are both different and important. (8)

  1. GPCR signaling independent of G proteins

Also known as the seven-transmembrane receptors or G protein-independent signaling, debunk the claim that G proteins are needed for signaling. If you look at the angiotensin ll at its AT1 receptor it activates both β-arrestin and G proteins. Even when angiotensin receptor blockers attach at the site blocking signaling, other antagonists may engage and block only one certain pathway, so we need to be critical in utilizing the appropriate outlay for each clinical condition. (8)

  1. Differential receptor phosphorylation

This explains the effects of characteristic fingerprinting of receptor. Each receptor has a specified fingerprint which allows different signaling to be sent out leading to a different phenotypical response. Differential phosphorylation has come into place due to receptor mutations leading to different responses to GPCR activation. This will lead to increased possibilities to influence their conformational recruitment to activate signaling pathways. (8)

  1. Receptor oligomerization

This concept refers to receptors that are inactive in binding or signaling but can become active as oligomers (“homomeric/heteromeric receptors”) or those that are intrinsically active as monomers having new activities as oligomers (as “receptor homomers/ heteromers.”). Receptor oligomers are formed in vivo. Another method of receptor oligomerization is by a process called “transactivation” in which two defected receptors oligomerized can combine and restore receptor functionality. This could allow a major breakthrough in understanding and curing disease. An example would be the cannabinoid receptor 1 antagonist/inverse agonist. This was initially developed to help cessation of smoking preventing nicotine addiction, but its side effect was suppression of appetite. “Research showed that cannabinoid receptor 1 dimerizes with the appetite-stimulating orexin-1 receptor and rimonabant antagonizes orexin A stimulation of ERK 1/2 through the orexin-1 receptor.” (8)

  1. Regulation of GPCR Membrane Expression.

-          Pharma cochaperones: rescue of mutant and under expressing GPCRs. These are small hydrophobic molecules hat penetrate the cell membrane binding to the nascent GPCR and saving the under expressing GCPR’s to the membrane. Such antagonists can help facilitate receptor mutations directed at outlining receptor function, an example being the mutant human GnRH receptor responding to the GnRH after preincubation with GnRH antagonist. This allows functionality to be restored. (8)

-          Novel pancreatic β-cell GPCRs Many GPCR’s in the pancreatic cells have shown potential to stimulate or inhibit the insulin secretion of these cells. The GLP1 is an example of these GPRC receptor that are used for the treatment to type ll diabetes. The GLP1 receptor increases the amount of calcium intracellularly indirectly leading to the production of insulin secretion. (8) Among the other GPCRs in β-cells are the free fatty acid receptors, GPR40, 43, and Various tested glitazones reveal different effective doses and time frames of activation underlining the variations and effectiveness of each. (8)

  1. We know the 2-dimentional and 3-dimentional of some of the GPCR’s. A large amount approximately 800 different types of GPCR are still unknown, these are known as orphan GPCRS’s. The deorphanization of non-olfactory GPCRs is an ongoing process and is promising in the pharmaceutical industry. As time goes on the number of orphan GPCR’s decrease. (9)


  “The structure of a GPCR can be divided into three parts: The first part is the extra-cellular region, consisting of the N terminus and three extracellular loops (ECL1–ECL3). The second part is the TM region, consisting of seven a-helices(TM1–TM7). The final part is the intracellular region, consisting of three intra-cellular loops (ICL1–ICL3), an intracellular amphipathic helix (H8), and the C terminus.” (7) GPCRs are membrane-bound receptor proteins consisting of seven α-helical transmembrane motives, three extracellular loops and three intracellular loops, which are responsible for the coupling with a heterotrimeric G-protein. GPCRs can be clustered into 5 families: “the rhodopsin family (701 members), the adhesion family (24 members), the frizzled/taste family (24 members), the glutamate family (15 members), and the secretin family (15 members).” (7)

Image 1: Diagram of a common GPCR (“Protein Actions: Principles and Modeling” Textbook)

Rhodopsin is one of the families of GPCR which contains 701 members. These are protiens which are liked to pigment carrying substance that is contained in the light- sensitive cells of the rod type in the retina of the eye. (5) The pigment contains a portion of rhodopsin which is retinal. It’s a substance which is formed by oxidation of vitamin-A. The structural insight of rhodopsin is based on high resolution in its inactive state. Large quantities of rhodopsin can be obtained easier than any other GPCR. Rhodopsin is better suited for structural studies and is stable, as it doesn’t denature under conditions which might denature other GPCR. (5) The first structure of rhodopsin was a two-dimensional crystal of bovine rhodopsin. Even though the structure was limited, it provided the first structural picture of the orientation of the TM segments in a lipid environment. (5) These provided the most basic template of the molecular model of GPCR. More recently the three-dimensional crystal structure of Rhodopsin has been obtained. (5)  In the 3-dimentional diagram, the 7-TM helical segments are linked together by extracellular and cytoplasmic loops. the amino-terminal tail is extracellular and the carboxy- terminal tail is cytoplasmic. The extracellular boundary of the plane of putative membrane bilayer is closer to the 11-cis-retinal chromophore. (5)

Image 2: 2-dimensional structure of Rhodopsin (https://en.wikipedia.org/wiki/G_protein-coupled_receptor)

Image 3: 3-dimensional structure of Rhodopsin (Jmol)

Image 4: Different types of GPCRs (Lecture slides)

All of these four structures represent antagonist-bound, inactive, conformations of four different G-protein-coupled receptors. “The structures are related as they all have a homologous seven-helix TM bundle but differ in the details of their binding sites and structures at both and extracellular surfaces.”


 As technology advances there are promising factors which would facilitate the crystallization of additional GPCRs and the solving of their structures. (8). “solving these challenges will provide insights into common and unique structural features involved in receptor activation, ligand binding, and interactions with signaling proteins.” (8) This will then guide in determining the unsolved GPCR structures more accurately. (8)  The development of small-molecule analogs and in silico discoveries are closer to reality due to more insight of the GPCR structure and function. (8) Interactions between GCPRs and intracellular protein point to an almost unlimited potential for the modulation of their expression, ligand selectivity and signaling to produce an array of cellular and physiological phenotypes. (8) Generation of knockout and hypomorph animals for every GCPR along with the discovery of GCPR ligand analogs and the modulators of GCPR function will provide early preclinical tools for defining physiological function and regulation. With understanding the Deorphanization of GPCR’s in advance stage, this offers exciting possibilities to discover new regulators of the endocrine system. (8) GPCR are a large family of cell surface receptors which respond to a variety of external signals. (8) GPCR’s are very important in sustaining human beings and even though a lot is unknown about the receptor, it has helped a lot in the pharmaceutical field. (10) The challenges in the future will be formidable and determining the structures of substantial numbers of GPCRs is not very likely in the near future, but the goal is to try hard and somehow achieve the desired result through trial and error.


1)      GPCR. (n.d.). Retrieved December 1, 2018, from https://www.nature.com/scitable/topicpage/gpcr-14047471

2)      Kroeze, W. K., Sheffler, D. J., & Roth, B. L. (2003, December 15). G-protein-coupled receptors at a glance. Retrieved December 1, 2018, from http://jcs.biologists.org/content/116/24/4867

3)      Kristiansen, K. (2004, July). Molecular mechanisms of ligand binding, signaling, and regulation within the superfamily of G-protein-coupled receptors: Molecular modeling and mutagenesis approaches to receptor structure and function. Retrieved December 1, 2018, from https://www.ncbi.nlm.nih.gov/pubmed/15251227

4)      Jogalekar, A. (2012, October 10). G Protein-Coupled Receptors (GPCRs) win 2012 Nobel Prize in Chemistry. Retrieved December 1, 2018, from https://blogs.scientificamerican.com/the-curious-wavefunction/g-protein-coupled-receptors-gpcrs-win-2012-nobel-prize-in-chemistry/

5)      Answers Ltd. (2018, November 22). G Protein Coupled Receptors | Essay. Retrieved December 1, 2018, from https://www.ukessays.com/essays/biology/g-protein-coupled-receptors-biology-essay.php

6)      Katritch, V., Cherezov, V. & Stevens, R. C. Diversity and modularity of G protein-coupled receptor structures. Trends Pharmacol. Sci. 33, 17-27 (2012)

7)      Klöpffer, W. (2002). The areas of protection debate (doi: Http://www.scientificJournais.com/db/PDF/ehs/2002.03/ehs2002.03.014.pdf). The International Journal of Life Cycle Assessment, 7(2), 94-94. doi:10.1007/bf02978852

8)      L. Newton, C., & P. Millar, R. (2010, January 1). The Year In G Protein-Coupled Receptor Research. Retrieved December 1, 2018, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428143/

9)      G protein-coupled receptor. (2018, November 12). Retrieved December 1, 2018, from https://en.wikipedia.org/wiki/G_protein-coupled_receptor

10)  G-protein Coupled Receptors. (n.d.). Retrieved December 1, 2018, from https://courses.washington.edu/conj/bess/gpcr/gpcr.htm


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