Receptor Highlight Series: G-protein Coupled Receptors

Hello and welcome to the very first post of the receptor highlight series! My plan for these will be to introduce you to a new receptor type, provide some examples, and showcase some real-world applicability of them in action.

This article highlights one of the most widely studied receptor families in drug discovery: G-protein-coupled receptors (GPCRs)! These receptors are sometimes called "7 transmembrane receptors" due to their homology in crossing the cellular membrane 7 times. While there are multiple ways to categorize these receptors, for our purposes, we will focus on the associated alpha subunits including G_s, G_i, and G_q. Located on the intracellular side of the membrane, these G-proteins are heterotrimeric, consisting of three subunits: the alpha subunits mentioned above, a beta subunit, and a gamma subunit.

In a resting state, the alpha subunit is tagged with a GDP (guanosine diphosphate) molecule, which stabilizes its association with the beta and gamma subunits, forming that heterotrimeric complex. Upon receptor stimulation, conformational changes to the intracellular portion of the receptor lead to a replacement of the GDP with a higher energy GTP (guanosine triphosphate). At this point, the outcomes depend on which G protein the receptor is coupled with. With this GTP molecule, a G_s-coupled receptor will go on to activate adenylyl cyclase, an enzyme that converts ATP (adenosine triphosphate) to cAMP (cyclic adenosine monophosphate), a secondary messenger. This increase in cAMP will ultimately activate PKA (protein kinase A) leading to the phosphorylation of all kinds of different proteins, further downstream signaling effects, and changes in cellular function. The generation of this signaling pathway is why people often refer to the G_s receptors as "stimulatory"!

An easy example of a G_s-coupled receptor is the β₁ receptor, which can be found on the surface of cardiac muscle cells. Normally, during a "fight-or-flight" event, such as in a high-stakes situation like a boxing match, adrenergic stimulation of β₁ receptors by epinephrine or norepinephrine will cause an increase in heart rate and contractility to ensure adequate blood flow to support the heightened demand of muscle tissues.

In contrast, G_i-coupled receptors actually inactivate adenylyl cyclase. By inhibiting adenylyl cyclase, ATP will not be converted to cAMP, and no downstream signaling will occur. For this reason, people often refer to G_i receptors as "inhibitory"!

Building on the earlier "fight-or-flight" example, a key G_i-coupled receptor is the adrenergic α₂ receptor, which can be found pre-synaptically on adrenergic neurons. After the boxing match—or any intense activity—your body transitions to a "rest-and-digest" state. In that "fight-or-flight" response, the release of norepinephrine is regulated through a negative feedback mechanism involving the G_i-coupled α₂ receptor. This helps communicate to the neurons to stop releasing norepinephrine, thus dampening the sympathetic response. Pretty cool that a single neurotransmitter/hormone can have completely different effects depending on the receptor it activates!

G_q on the other hand stands a bit unique compared to the other two. While it similarly will require receptor stimulation and GDP to GTP interchange on the alpha subunit of the G-protein, the target of that alpha subunit is NOT adenylyl cyclase, but PLC (phospholipase C). PLC functions to break apart phospholipids like PIP₂ (phosphatidylinositol 4,5-bisphosphate) which is broken down into IP₃ (inositol 1,4,5-trisphosphate) which helps to release calcium from the endoplasmic reticulum and DAG (Diacylglycerol) which activates PKC (protein kinase C). This ultimately sends an intracellular signal leading to downstream effects, though distinct from those generated by the G_s receptors we talked about before.

Back to the "fight-or-flight", G_q receptors like adrenergic α₁ receptors, are present on the surface of smooth muscle cells of blood vessels. In the afferent arterioles, α₁ receptors will help regulate blood flow to the glomerulus where filtration occurs, an early step in urine production. If these receptors are stimulated, the afferent arterioles will constrict and will "turn off" that urine production! I mean... Peeing yourself wouldn't be too helpful for fending off an opponent in a boxing ring right?

I hope you enjoyed this first deep dive into receptor biology! If you’re curious to learn more, consider exploring the lesser-known G_12/13 receptor subtype. It's associated with wound healing, the immune response, and cancer metastases. Regardless, stay tuned for next month’s highlight, where we’ll explore another fascinating receptor type. See you then!

*Information presented on RxTeach does not represent the opinion of any specific company, organization, or team other than the authors themselves. No patient-provider relationship is created.