G Protein-Coupled Receptors

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

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

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

Another important G-protein target is phospholipase C. This protein catalyzes the generation of DAG (diacylglycerol) and IP3.¹

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.

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

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.

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

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

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.