Science for all May 2018 This week: Pharmacology

Understanding G protein coupled receptors

You may have stumbled onto this blog because you wanted to increase your knowledge about GPCR’s or maybe even try to learn what it actually is and how it works. Well, whatever your intentions, you have certainly come to the right place! GPCR’s are essential to our physiological well-being because they clinically transform the extracellular stimuli we receive on a daily basis into intracellular signals [8]. They can be subject to a diverse range of stimuli including odorants, light, smells, hormones, nucleotides, lipids, amino acids and indisputably, many more to come. The investigation and study of GPCR’s has been prolonged due to its pharmacological complexity, however, Robert Lefkowitz and Brian Kobilka have provided ground-breaking discovery revealing the conceptual understanding of how GPCR’s function. [11] Let’s start small! So, what is a receptor? In general terms, a receptor can be defined as a recognition molecule that can detect changes in the external environment. Receptors can be found in our sensory organs such as the eyes, skin, nose and ears. Each of these organs contain receptors sensitive to a specific type of stimuli. For example, receptors located in our nose will be sensitive to any chemical modifications in the surrounding air. However, when defining a receptor in pharmacological terms, it can be described as a target molecule with which a specific molecule (e.g. a drug, hormone, or neurotransmitter) has to combine with in order to initiate a cellular response [4]. These molecules (either the drug, hormone or neurotransmitter) are referred to as ligands. Receptors and ligands can appear in many shapes, however, they all contain one attribute in common: they present themselves as closely matched pairs. To illustrate, receptors acknowledge only one (maybe a few) distinct ligands, and a ligand binds to only one (maybe a few) target receptors. The binding action between the ligand and receptor can establish a molecular change in the receptor’s shape and activity. This enables it to generate a signal or instantaneously assemble an altercation within the cell. [9] What is a gpcr?

G protein-coupled receptors are cell surface receptors that respond to a variety of stimuli, hence playing a fundamental role in mechanical, physical, and biochemical functioning. The most imperative characteristic about GPCRs is that they comprise of seven transmembrane domain receptors which transmit signals inside the cell through the G protein [5]. Because this structural characteristic is quite distinctive, they are also called “seven transmembrane receptors”. When examining GPCRs we need to acknowledge G proteins. G proteins are proteins that have the capability to bind to the nucleotide GTP (Guanosine triphosphate) which is then broken down through hydrolysis to construct GDP (Guanosine diphosphate). A G protein connected to a GTP is active (or on) however, a G protein linked to a GDP is inactive (or off). All of the G proteins related to GPCRs are composed of three distinctive subunits considered as heterotrimeric G proteins. These are called alpha, beta and gamma. [7]

GPCRs are only found in eukaryotes! [5]

Drawings [4]

How do they work? [8], [4], [7] 1) The GPCR waits at its inactive state, expecting a

signalling molecule. When the ligand molecule binds to the GPCR, the alpha subunit found in the heterotrimeric G protein exchanges GDP for GTP. The GPCR is now activated

2) Once the alpha subunit is attached with the GTP, it

separates itself from both the beta and gamma subunits. The subunits can further combine with effectors (either an enzyme or ion channel). The alpha-GTP segment often activate (or inhibit) enzymes, producing a secondary messenger. The beta-gamma component can interact with another effector, also impacting cellular activity

3) Hydrolysis occurs, transforming the GTP back into GDP (GTP loses a phosphate molecule). This then alerts the ligand to disconnect with the receptor

4) During the last step, the alpha subunit re-joins the GPCR. The beta and gamma subunits also reunite with the alpha subunit. Therefore, the GPCR returns to its inactive state

Produces secondary messenger – E.g: cAMP

GPCR and Epinephrine (adrenalin): Let’s say you’re about to take an important exam in 5 minutes. Common feelings associated with this phenomenon could be stress or fear of failure. You start to feel your heart beat faster, your breathing rapidly increases and your blood pressure rises [6]. This is known as the ‘fight or flight’ response [3]. All these physiological modifications eventuate due to the release of epinephrine by the adrenal glands [2]. Basically, this response supplies a rush of energy which prepares the body to either fight or flee when exposed to a stressful situation. How do these chemical and physical situations occur? Firstly, once the epinephrine is released, it binds to a type of GPCR known as an adrenergic receptor. The alpha-subunit contained in the heterotrimeric G protein will then swap out its GDP for GTP. The GTP-alpha (now activated) segment separates itself from the beta-gamma complex to find an effector. In this case, the enzyme it stimulates is referred to as adenylyl cyclase. The adenylyl cyclase will then convert ATP into cAMP (second messenger) increasing its intracellular content. cAMP is ultimately responsible for producing these metabolic responses to stress [7].

GPCRs are the targets of approximately 30-50% FDA-approved drugs. [1]

   References: [1] Babu, M.M., Chavali, S., Gloriam, D.E., Hauser, A.S., Jahn, L.J., Martemyanov, K.A., Masuho, I. 2018,

‘Pharmacogenomics of GPCR Drug Targets’, Journal of MRC Laboratory of Molecular Biology, vol. 172, viewed 3 May 2018, <https://www-sciencedirect-com.ezproxy.lib.uts.edu.au/science/article/pii/S0092867417313843?via%3Dihub>

[2] Baltimore, D., Berk, A., Darnell, J., Lodish, H., Matsudaira. P., Zipursky, S. 2000, G Protein –Coupled Receptors and Their Effectors, Molecular cell biology: fourth edition, W. H. Freeman and Company, New York, viewed 8 May 2018, <https://www.ncbi.nlm.nih.gov/books/NBK21718/>

[3] Fight-or-flight response 2016, Britannica Academic, Encyclopaedia Britannica, viewed 8 May 2018,

<academic-eb-com.ezproxy.lib.uts.edu.au/levels/collegiate/article/fight-or-flight-response/474693> [4] Flower, R.J., Henderson, G., Rang, H.P., Ritter, J.M. 2016, Rang and Dale’s Pharmacology, 8th edition,

Elsevier limited: Churchill livingstone, UK. [5] Gurevich, V., Gurevich, E. 2017, ‘Molecular Mechanisms of GPCR Signaling: A Structural Perspective’,

International journal of molecular sciences, vol. 18, viewed 2 May 2018, <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751122/>

[6] Karriem-Norwood, V. 2017, Stress symptoms, WebMD Medical Reference, viewed on 5 May 2018,

<https://www.webmd.com/balance/stress-management/stress-symptoms-effects_of-stress-on-the-body#2>

[7] Khan academy medicine 2014, G Protein Coupled Receptors - Nervous system physiology, videorecording, YouTube, viewed 4 May 2018, <https://www.youtube.com/watch?v=ZBSo_GFN3qI>

[8] Kroeze, W.K., Roth, B.L., Sheffler, D.J. 2003, ‘G-protein-coupled receptors at a glance’, Journal of cell

science, vol. 116, viewed 2 May 2018, <http://jcs.biologists.org/content/116/24/4867>

[9] Ligands and receptors 2018, Khan academy, viewed 2 May 2018, <https://www.khanacademy.org/science/biology/cell-signaling/mechanisms-of-cell-signaling/a/signal-perception>

[10] Robinson, B., Hilton, L. 2009, An introduction to receptor pharmacology, The University of Nottingham,

England, viewed 5 May 2018, <https://www.nottingham.ac.uk/nmp/sonet/rlos/bioproc/intro-receptor/> [11] Smart receptors on cell surfaces, 2012, NobelPrize.org: the official website of the nobel prize, USA, v

viewed 2 May 2018, <https://www.nobelprize.org/nobel_prizes/chemistry/laureates/2012/press.html>