Signal transduction is an essential part of our bodily functions. Our cells need to be able to communicate with one another and respond to signals effectively. The process by which our cells communicate and carry out essential life functions is known as signal transduction. During signal transduction, cells send out signals in the form of chemical ligands, and these ligands bind to receptors on another cell's surface or within the cell's cytosol. There is a wide array of receptor groups in the body that each have different functions. The receptor group that we will be discussing in this article is the G protein-coupled receptors.
G-protein coupled receptors' location
G-protein coupled receptors are specialized receptors located at the cellular membrane. These special receptors are bound to G proteins located on the cell's intracellular side.1
G-protein coupled receptors are the largest and most diverse group of cellular membrane receptors in eukaryotic cells.1 They recognize signals such as light, ligands, and proteins and induce a wide variety of signal cascades in the target cell. G-protein couple receptors also have other functions within the cell and have important effects on pharmaceutical treatment.
Researchers estimate that approximately one-third of all pharmaceuticals work by interacting with G-protein-coupled receptors.1
G-protein coupled receptors function
So what is the function of G-protein coupled receptors? Well as their name suggests, they interact with G protein in the target cell's plasma membrane. When a ligand binds to a G-protein coupled receptor, conformational changes occur within the G-protein receptor.1 These changes trigger the receptor to interact with a nearby G protein.
G- proteins are specialized proteins that are capable of binding guanosine triphosphate (GTP) and guanosine diphosphate (GDP). Some G proteins act as signaling proteins and are comprised of a single subunit; however, G proteins that make up G-protein-coupled receptors are heterotrimeric.1
Heterotrimieric: A protein that consists of three different subunits: alpha, beta, and gamma.
The alpha subunit of the G-protein coupled receptor binds GTP or GDP depending on if the receptor is activated by a ligand.1 In the absence of the ligand signal, GDP is attached to the alpha subunit and the entire G-protein-GDP complex is bound to the G-protein coupled receptor.1
This phenomenon is where GPCRs get their name.
Once a GCPR is bound by a ligand, GDP is replaced by GTP on the alpha subunit.1 This causes the G-protein to break up into two components: the GTP-bound alpha subunit and the beta-gamma dimer.1 Both parts of the receptor continue to be attached to the plasma membrane but are no longer bound to the membrane receptor.1 This allows the subunits to interact with other membrane molecules and proteins. G-proteins remain active as long as GTP is bound to the alpha subunit. When GTP is hydrolyzed back into GDP, the entire G-protein joins together and rebinds to the membrane receptor.1
G-protein coupled receptors diagram
When a G-protein is activated, both components can send messages in the cell by interacting with other proteins or molecules involved in signal transduction. G-protein components may target specific enzymes and ion channels in order to activate second messengers. Some G-proteins can cause excitation of the target cell while others have inhibitory functions.1
Second messengers
Second messengers are small molecules or ions that relay signals from membrane receptors into the target cell to potentiate the signal within the cell's cytosol.1 The activation of a single G-protein can generate a wide array of second messengers such as cyclic AMP (cAMP) and inositol triphosphate (IP3).1
A common target of G-proteins is adenylyl cyclase which is a membrane enzyme responsible for catalyzing the synthesis of cAMP.1
cAMP plays important roles in the brain such as relay of motor information and responses to sensory information, and hormone activity.1
Another important G-protein target is phospholipase C. This protein catalyzes the generation of DAG (diacylglycerol) and IP3.1
The production of these two-second messengers have vital roles in many bodily processes needed to maintain homeostasis.
G-protein coupled receptors examples
As previously mentioned, there is a wide range of G-protein coupled receptors in the human body each with different effects on the cells to that they are bound. Some G-protein coupled receptors are muscarinic acetylcholine receptors and dopamine receptors.
- Muscarinic acetylcholine receptors play vital roles in nerve transmission in the peripheral nervous system while, as the name suggests,
- dopamine G-protein coupled receptors function to bind to and transmit signals from dopamine.
These receptors have been widely studied in addiction as researchers believe that variations in dopamine receptor subunits lead to stronger addictive patterns in humans with certain subunit variants.
Let's take a look at the steps involved in these receptor pathways.
G-protein coupled receptors steps
In the previous section, we discussed a few G-protein coupled receptors and the roles they play in the human body. Let's take a look at the steps involved in these receptor pathways to learning more about these special G-protein coupled receptors.
Muscarinic acetylcholine receptors
Muscarinic receptors are cholinergic receptors which means that they are able to acetylcholine. What is interesting, is that these G-protein coupled receptors can also bind the neurotoxin muscarine which is secreted by poisonous mushrooms.2
This is why these receptors are called muscarinic.
There are five subtypes of muscarinic Ach receptors but only three of them are functional within the human body these subtypes are: M1, M2, and M3.2
These subtypes are present in the peripheral nervous system ganglia and in autonomic effector organs such as the heart and brain.2 Within the cells of these organs or ganglia, the muscarinic receptor is bound to G-protein. Once activated by the binding of acetylcholine, the G-protein becomes activated and GDP is converted into GTP.
Now from the previous section, we know that once a G-protein is activated, it breaks up into two components where the component with the alpha subunit remains bound to the GTP forming a complex.
Once the complex is formed, it travels to activate the phospholipase C enzyme.2 As phospholipase C is activated, the second messengers IP3 (inositol triphosphate) and DAG (diacylglycerol) are produced.2
IP3 is responsible for initiating Ca2+ influx into the cell causing the cell to be stimulated.
Meanwhile, DAG is responsible for the activation of protein kinase C (PKC).2
Once activated PKC phosphorylates numerous cellular proteins leading to further signal cascades within the cell.2
Dopamine G-protein coupled receptors
Dopamine G-protein receptors are responsible for binding to dopamine and relaying excitatory signals through target cells.3 Since dopamine is the reward neurotransmitter, dysfunctions of these types of receptors lead to various mental diseases.3 There are 4 different subtypes of dopaminergic receptors which are DRD1-DRD4.3
For the purpose of this article, we will be discussing the DRD1 receptor signal transduction.
Activation of the DRD1 dopaminergic receptor stimulates the activation of the enzyme adenylyl cyclase. This enzyme converts ATP into the second messenger cAMP.3 CAMP is responsible for activating protein kinase A (PKA) which phosphorylates and activates transcription factors such as CREB AND ATF1 that function to change the gene expression of the target cell.3
CREB: cAMP-response element binding protein. It is an intracellular protein that regulates genes important for the function of dopaminergic neurons.
ATF1: Cyclic AMP-dependent transcription factor. It is another intracellular transcription factor that controls the expression of certain genes in neurons and other cells.
Now, the actual pathways are a lot more complicated involving numerous steps that you will not have to know but it is good to develop a working understanding of how G-protein coupled receptors participate in signal transduction signaling cascades.
G Protein-Coupled Receptors - Key takeaways
References
- Nature Education, G-protein Coupled Receptors, Nature, 2014.
- Sara The Pharmacist, Muscarinic Receptors, 2019.
- Undieh A. S., Pharmacology of signaling induced by dopamine D(1)-like receptor activation. Pharmacology & therapeutics, 128, 2010.
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