How Do G Protein Coupled Receptors Work

G-protein-coupled receptors (GPCR) are the most diverse group of membrane receptors in eukaryotes. The main function of GPCRs is to detect light energy or nutrients outside the cell and to activate signal transduction pathways inside the cell. Ultimately, GPCRs trigger cellular responses. The agonists (chemicals that bind to a receptor to produce a cellular response by activating the receptor) that binds to the GPCR can be a hormone, neurotransmitter or an external stimuli such as an odor or a pheromone. Upon binding an agonist, the GPCR activates the associated G protein for the initiation of a particular cellular mechanism.

Key Areas Covered

1. What is G Protein Coupled Receptor
     – Definition, Structure, Role
2. How Do G Protein Coupled Receptors Work
     – Mechanism of G Protein Activation

Key Terms: Effector Enzyme, G Protein, GDP (Guanosine Diphosphate), G-Protein-Coupled Receptors (GPCRs), GTP (Guanosine Triphosphate), Second Messengers

How Do G Protein Coupled Receptors Work (1)

What is a G Protein Coupled Receptor

The G-Protein-Coupled Receptors (GPCRs) are the largest class of membrane proteins in eukaryotes, which mediate most of the physiological responses of hormones, neurotransmitters, and environmental stimulants. They are also responsible for vision, sense of smell and taste. One of the key features of GPCRs is the presence of seven membrane-spanning α-helices that are interconnected by alternative intracellular and extracellular loop regions. A human GPCR is shown in figure 1.

How Do G Protein Coupled Receptors Work - 2

Figure 1: GPCR

The main role of a GPCR is to activate a heterotrimeric G-proteins upon the binding of an agonist to the receptor.

How Do G Protein Coupled Receptors Work

GPCRs are a type of receptors found on the cell membrane. When the agonist binds to the GPCR, a series of reactions take place to trigger a cellular response. The steps involved in triggering a cellular response by the activation of GPCR are described below.

  1. When the G-Protein-Coupled receptor is not bound to an agonist, it remains inactive. The G protein also remains inactive on the cell membrane. The three subunits of G protein are Gsα, Gβ, and Gγ. The inactive state of the G protein contains a bound GDP to the Gsα domain.
  2. Upon binding of a ligand/agonist such as hormones or neurotransmitters, the GPCR undergoes a conformational change, activating its GEF domain. The change in the conformation in the GPCR allows the binding of G protein to the GEF domain. The GDP of the G protein is replaced by a GTP by the action of GEF domain, activating the G protein. The GEF domain activates monomeric GTPase to replace GDP from a GTP.
  3. Upon activation, the Gsα domain dissociates from the GPCR-G protein complex and binds to the effector enzyme on the cell membrane to activate it. The activated effector enzyme can be adenylyl cyclase, phospholipase C, etc. It generates second messengers such as cAMP, inositol 1,4,5-triphosphate, 1,2-diacylglycerol, etc. These second messengers activate various types of proteins in the cytosol to generate a particular cellular response. Second messengers are the initiating components of the intracellular signal transduction cascades, which activates a particular cellular mechanism.
  4. The hydrolysis of GTP into GDP in the Gsα domain dissociates from the effector enzyme, deactivating the enzyme.

The mechanism of action of the GPCR is shown in figure 2.

How Do G Protein Coupled Receptors Work

Figure 2: GPCR Mechanism of Action


The G-protein-coupled receptor is the most abundant type of receptors on the cell membrane of eukaryotes. It mediates cellular functions upon the activation by the binding of agonists such hormones, neurotransmitters or external stimuli. The activation of GPCR leads to the activation of G protein on the cell membrane. The activated G protein binds to an effector enzyme on the cell membrane to generate second messengers that trigger cellular responses in the cytosol.


1. “GPCR.” Nature News, Nature Publishing Group, Available here.

Image Courtesy:

1. “Beta-2-adrenergic-receptor” By Opabinia regalis – Own work (CC BY-SA 3.0) via Commons Wikimedia
2. “G protein” By Tpirojsi – Own work (Public Domain) via Commons Wikimedia

About the Author: Lakna

Lakna, a graduate in Molecular Biology & Biochemistry, is a Molecular Biologist and has a broad and keen interest in the discovery of nature related things

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