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Original Author(s): Rosamund Nicholson
Last updated: 4th May 2021
Revisions: 15

Original Author(s): Rosamund Nicholson
Last updated: 4th May 2021
Revisions: 15

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G-protein coupled receptors are a diverse family of receptors found in a huge range of tissues throughout the body. They function to respond to a wide variety of extracellular signals, such as hormones or neurotransmitters, and trigger intracellular signalling cascades, which regulate a wide range of bodily functions. This article will discuss the structure and function of GPCRs in the human body.

Structure

G-protein coupled receptors are composed of a transmembrane region crossing the lipid bilayer seven times (hence they are also be referred to as 7-transmembrane receptors). This transmembrane region is coupled with a G-protein. GPCRs have no integral enzyme activity or ion channel, therefore all their downstream effects are mediated via their G-protein.

Figure 1 – G protein structure and activation cascade

The G-protein is heterotrimeric and is made up of three different subunits: alpha (α), beta (β) and gamma (γ). In its inactive state, GDP is bound to the α-subunit of the G-protein.

There are hundreds of GPCRs in the genome and their receptors are activated by many signals such as neurotransmitters, hormones, ions, peptides and even photons in the retina. Common examples of GPCRs include adrenoreceptors, muscarinic acetylcholine receptors and opioid receptors.

There are also many different types of α-, β- and γ-subunits. This allows for many GPCR combinations created by different receptors being coupled with G proteins comprised of different subunits. Furthermore, one GPCR can be associated with many G proteins, hence one signal can have many downstream cellular reactions.

Ligand Binding

An agonist (ligand) is a substance which binds to a receptor and brings about a cellular response. For G-protein coupled receptors, this consists of 5 main steps.

  1. Ligands bind to the extracellular portion of the G-protein coupled receptor, binding either at the N-terminus or a binding site within the transmembrane region.
  2. Binding at the extracellular ligand binding site causes a conformational change in the GPCR, resulting in release of GDP from the α-subunit of the G-protein.
  3. Released GDP is then replaced with a GTP
  4. This activates the G-protein, causing the α-subunit and bound GTP to dissociate from the transmembrane portion of the GPCR and βγ-subunit.
  5. These α-subunit interacts with its relevant effectors and cause downstream effects, e.g. ion channel opening or enzyme activity regulation.

Despite the fact that one G-protein coupled receptor only contains one α-subunit, this can interact with several secondary messengers, which can in turn activate multiple enzymes and catalyse many reactions. This creates a cascade response whereby one agonist binding to the GPCR can bring about the catalysis of many reactions (signal amplification).

Figure 2 – Sequence following GPCR ligand binding

To prevent excess signalling, GPCR activity can be switched off. GTPase catalyses the breakdown of GTP on the α-subunit into GDP + Pi. GDP increases the α-subunit’s affinity for the βγ-subunit, allowing reformation of the heterotrimeric complex of the G-protein. The G-protein then reassociates with the transmembrane receptor, reforming the GPCR for the next ligand binding.

Types of G-protein

There are several different types of G-protein that can be present in a GPCR, which vary based on their α -subunit. Each alpha-subunit stimulates an enzyme, which acts to either increase or decrease the concentration of a secondary messenger. This goes on to impact a downstream effector, which then causes a cellular response. The ultimate effect of these proteins depends on the specific cell in which it is located.

Alpha subunit Enzyme Secondary messenger Effector
GS Stimulates adenylyl cyclase, which catalyses conversion of ATP to cyclic AMP Increases cAMP Stimulates PKA activation (cAMP-dependent protein kinase), which goes on to phosphorylate target proteins
Gi Inhibits adenylyl cyclase, which catalyses conversion of ATP to cyclic AMP Reduces cAMP Inhibits PKA activation (cAMP-dependent protein kinase)
GQ or G11 Stimulates phospholipase C, which cleaves PIP2 in the cell membrane into IP3 and DAG Increases IP3 and DAG IP3 opens calcium channels, causing a Ca2+ efflux into the cytoplasm

 

DAG activates protein kinase C (PKC), which goes on to phosphorylate target proteins

 

Clinical Relevance: Pharmacological Targeting of GPCRs

One of the most common places to find GPCRs clinically is in the autonomic nervous system. There are four common adrenoreceptors in the sympathetic nervous system (α1, α2, β1 and β2) and three common muscarinic receptors in the parasympathetic nervous system (M1, M2 and M3). These are all GPCRs and a pneumonic to remember which receptor has which α-subunit is ‘kiss quick’ (spelt QISS QIQ):

  • Q – α1
  • I – α2
  • S – β1
  • S – β2
  • Q – M1
  • I – M2
  • Q – M3

Many common medications act at adrenoreceptors or muscarinic receptors. An example of this are the beta blockers, a class of drug which act as antagonists at the adrenergic beta receptors, and are commonly used to slow the heart rate and manage arrhythmias. Conversely, agonists at the beta-adrenergic receptor can be used to open up the airways in management of asthma.