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Cell-Signalling and Drug Targeting in One: The G-Protein Coupled Receptor

What is the G-protein coupled receptor?

Abbreviated to GPCR, this is the largest family of membrane proteins. A G-protein is a guanine nucleotide-binding protein meaning it is a protein containing the nucleotide guanine, that you may know from the bases in DNA that can bind to other molecules. Overall, it is a glycoprotein anchored on a cell membrane and the most important point - it’s a receptor. And it is composed of three different subunits, making it heterotrimeric. The three subunits are named alpha (α), beta (β) and gamma (Ɣ), each encoded by a variety of different genes. These subunits carry out different functions within a cell.

The GPCR is involved in signal transduction from the binding of a signalling molecule on the cell surface to the effect generated within the cell. Signal transduction involves the conversion of extracellular signals into intracellular signals. A signalling molecule is a ligand such as a hormone or a neurotransmitter that binds to the GPCR, activating it. This results in a cascade of events, after the binding of only one molecule! They can do this by the activation of 2nd messengers, which will be discussed later on.

Because there are so many processes involved, it makes the GPCR a perfect target for drug therapy. GPCR’s also regulate many of your bodily operations such as homeostasis, metabolism and growth. This means that if any of them start to fail due to disease, one of the main targets in restoring your health would be to target your GPCR’s.

GPCR's structure

The structure of a receptor determines its actions and therefore the consequences in the cell. More complex structures carry out more intricate and detailed procedures, like the GPCR.

The GPCR is described as metabotropic. Metabotropic means that the channels found in the membrane protein have no pore region. Pore regions are found in many proteins, such as ion channels which you may know a bit about. Instead, these channels use signal transduction mechanisms. Ligands don’t pass through them, they bind to them and activate other cellular processes. It is the structure of the GPCR that enables its function in this way.

Let’s have a look at Figure 1. This is what the GPCR looks like.

Figure 1: The structure of the G-protein coupled receptor. There are seven transmembrane domains connected by three extracellular loops and three intracellular loops. The N-terminus of the polypeptide is present on the outside of the cell, and the C-terminus is present on the inside. The pink rectangles represent where a ligand could bind on the receptor, making them the ligand-binding sites. The green rectangle is where the G-protein would bind to. Adapted from: Chemokine Receptors – One Kind of Powerful Seven Transmembrane Spanning G Protein-coupled Receptor-CUSABIO

The GPCR has seven transmembrane domains, meaning there are seven domains that span across either side of the phospholipid membrane. They are hydrophobic (they don’t like water), just like the fatty acid tails of the phospholipid membrane so they fit perfectly in the membrane. There is a single polypeptide chain that connects each domain to the next, starting from the N-terminus, also known as the amino-terminus -NH2. The chain ends in the C-terminus that is a carboxyl group -COOH. As you can see in Figure 1, coloured rectangles represent ligand-binding sites and G-protein binding sites. The pink rectangles out of the cell near the N-terminus and between domains 2 and 3 are the only places where a ligand could bind. The only G-protein binding site is shown as a green rectangle in Figure 1.

Do all G-protein coupled receptors look the same?

There are three families of G-protein coupled receptors. They are the rhodopsin family, the secretin/glucagon family and the metabotropic glutamate receptor/calcium sensor family. Structurally, they are all extremely similar, apart from they have alternating lengths of the N-terminus chain. Here’s a bit about each family:

  • The rhodopsin family

This is the largest group of GPCR’s. Rhodopsin is a protein that is sensitive to light and contains a purple pigment. This means that these GPCR’s are present in the eye, in cells called rods of the retina. They have a short N-terminus.

  • The secretin/glucagon family

Secretin and glucagon are peptide hormones that bind to this family of receptors that are essential for bodily processes including the regulation of gastric acid, keeping it above 15mEQ/hr and the regulation of blood glucose levels, keeping it below 140mg/dL. It has an intermediate N-terminus length.

  • The metabotropic glutamate receptor/calcium sensor

This is the smallest group of the GPCR’s. Glutamate is an essential excitatory neurotransmitter in the brain, so it is essential that there is a GPCR family to detect this. It also acts as a calcium sensor which is necessary for the heart to function. It has the longest N-terminus.

Activation and signalling pathways

Different molecules activate different types of GPCR’s which arise to multiple cellular changes. All of the signalling pathways are vital in the function of your bodily processes. Let’s take a look at how these happen.

When there is no ligand or molecule bound to the receptor and it is in the resting state, the G-protein subunits are associated and bound to the receptor by lipid residues connected to the phospholipid membrane. GDP is chemically bound to the Gα subunit. You can see what this looks like in Figure 2.

Figure 2: An inactive GPCR. Gα, Gβ and GƔ are all bound to the receptor in the G-protein binding site. GDP is bound to the G-α subunit. There is no ligand bound to the ligand-binding sites which are on the N-terminus and between the second and third domains. Adapted from: Generalized example of GPCR signalling. A seven-transmembrane protein in... | Download Scientific Diagram (

When a ligand binds to the receptor, the following stages happen:

1. Dissociation

The α and βƔ subunits separate from each other, travelling in different directions. The βƔ subunit moves towards voltage-gated ion channels and the α moves to an area where it can exert different effects.

2. Conversion

GDP is converted to GTP by the addition of a phosphate group using pyruvate kinase and phosphoenolpyruvate. To switch the GDP to GTP, a guanine nucleotide exchange factor (GEF) is required. The ligand binding to the receptor causes this as the energy created passes through the Gα subunit to phosphorylate GDP into GTP. Its association to the Gα subunit allows the GTP to move.

3. Targeting

Both the Gα-GTP subunit and the GβƔ subunit then travel to their targets in the cell. This is where changes begin to happen.

As mentioned at the start, the G-protein consists of the three subunits ɑ, β and Ɣ. The β and the Ɣ units always remain together, so it is called the βƔ subunit. The α subunit prefers to stay on its own and can associate with the βƔ subunit and other proteins. For that reason, there are four different types of α subunits found in our cells, each with a different function.

Two molecules that are essential in the activation of GPCR’s are GTP and GDP. You may already be aware of ATP and ADP from school which are very similar to these molecules. The only difference is that the A in ATP and ADP stands for adenosine, whereas the G in GTP and GDP stands for guanosine - they’re similar molecules in structure - they’re both nitrogenous bases found in DNA (please cite this) but not the same.

What can the G-protein subunits do?

Depending on where they are in the body, many different actions occur. Let’s start with the simple one.

The βƔ subunit

It’s mainly known for activating potassium channels and inhibiting voltage-gated calcium channels. This will have a huge effect on the overall charge of a membrane, depending on the ion gradient meaning that the cell’s function will alter - it will stop working or promote its function until other components in the cell stop it. The channels let in ions that have a specific charge, for example, potassium ions have a charge of +1, usually written as K+. If a potassium channel opens, potassium ions flow out of cells down their concentration gradient and therefore decrease the membrane’s overall charge. This is important in the part of neuronal cells called synapses where signals are transmitted from one neuron to the next, transferring information from the nervous system to the rest of the body.

The α subunit

The four different Gα subtypes generate different cellular effects by recruiting different secondary messengers.

Now, what does the term ‘secondary messenger’ mean? A second messenger is a small molecule or ion which carries the signal generated by the ligand binding to the receptor and takes it to another molecule called an effector protein. Let’s take a look at the subtypes Gαs, Gαi, Gαo and Gαq; what secondary messengers they recruit and their overall effect on the cell:

  • Gαs

Adenylyl cyclase, an enzyme that causes the increase of secondary messenger cyclic AMP. This molecule is involved in the regulation of glycogen, sugar, and lipid metabolism. You would see Gαs associated with amine receptors, for example, some of the serotonin receptors in the brain. Another example would be when the body experiences pain, adenylyl cyclase synthesises cyclic AMP initiating signalling that mediates pain.

  • Gαi

This time, adenylyl cyclase is inhibited, resulting in a decrease of cyclic AMP production. An example when this is useful is in the treatment of pain following opioid receptor activation.

  • Gαo

This works cooperatively with the Gαi subtype, causing the same effects.

  • Gαq

Phospholipase C activation recruits the 2nd messenger’s inositol triphosphate (IP3) and diacylglycerol (DAG). Together these molecules increase intracellular calcium concentrations and change protein function.

So, those are the basics of what happens when a ligand binds to a GPCR. The results include a change in membrane potential, calcium release, protein phosphorylation or some other effects that determine the cell’s function.

Drug targeting

The GPCR’s and second messengers you are now aware of are what is targeted for the treatment of disease. Designing drugs that produce the effect the body can’t carry out on its own is what’s necessary to treat patients. Let’s explore the different drug targets of GPCR signalling pathways.

Adenylyl cyclase and cyclic AMP

Adenylyl cyclase is known for increasing concentrations of cyclic AMP. As mentioned earlier you know how important cyclic AMP is in the regulation of various processes in the human body. If the concentration levels of cyclic AMP differ from the usual set point, these functions will not work as efficiently as before, so drugs that activate or inhibit the associated receptors will help to restore the normal levels. Cyclic AMP can control these functions as it recruits protein kinase A upon activation. You may already know that when proteins become altered by phosphorylation their function changes, which is what leads to an overall change in molecular mechanisms found within a cell. Well, it is the protein kinases that phosphorylate these proteins.

Phospholipase C and inositol triphosphate

Inositol triphosphate’s (IP3) main role is the release of calcium ions from the storage organelles to cellular processes that require free calcium. Calcium ions are vital in many processes including contraction, secretion, enzyme activation and the change in the potential of a membrane (making it more negative - hyperpolarised). As well as IP3, diacylglycerol (DAG) is also activated in this pathway which recruits the enzyme similar to protein kinase A, protein kinase C, also involved in the phosphorylation of proteins. The variety of diseases that can be treated by activating this enzyme is huge.

Ion channels

You have heard a lot about calcium channels being affected by GPCR’s, but potassium channels can also be influenced. Potassium channels can be opened, allowing potassium ions to flow out of a cell, making it more negative intracellularly. The result of this is that action potentials cannot fire which means there is no signal transmission generated. A drug class that especially targets calcium and potassium voltage-gated ion channels are opioids. These are pain killers, the most famous one being morphine. Morphine binds to GPCR’s, activating potassium channels and inhibiting calcium channels so that the painful signal can’t be transmitted throughout the body.

Why should you care?

Many diseases target GPCR’s but let’s just take a look at one for now as an example. I’m sure you’ve heard of cholera, the disease caused by cholera toxin which is secreted by the bacterium Vibrio cholerae. Although rare in the western world, individuals that are infected with this bacterium become severely dehydrated by losing all of their water as diarrhoea. It does this by binding to the Gαs subunit, locking it in an active state, bound to GTP, resulting in the constant increase of cyclic AMP. The elevated levels drive ions and water out of the intestine as watery diarrhoea - not nice. In countries where healthcare is a luxury, most people die when infected due to extreme dehydration.

The point stressed is that, when these receptors are targeted in disease, the entire body is badly affected. This isn’t the only disease that targets the GPCR’s, inherited mutations can arise causing severe defects in GPCR signalling, for example, Retinitis pigmentosa causes blindness. There may be many diseases that you are aware of that you didn’t know were due to GCPR dysfunction.

If you haven’t realised by now, GPCR’s are extremely important in your body. They drive you to survive and thrive, operating in most systems by regulating them. The heart, smooth muscle, the brain and the liver have only been mentioned here, but there are many more tissues where GPCR’s are active and essential. It is astonishing what a small amount of the population knows about GPCR’s when their function is necessary for us to live.


Eve Littlejohns

BSc Biomedical Science

University of Bristol


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