GPCR/G Protein


What are GPCRs?


G protein-coupled receptors (or GPCRs) represent the largest family of membrane proteins in the human genome and are the target of approximately half of all therapeutic drugs. They are found only in eukaryotes, including yeast, choanoflagellates, and animals[1]. There are two principal signal transduction pathways involving the G protein-coupled receptors: the cAMP signal pathway and the phosphatidylinositol signal pathway.


Fig.1 The main signaling pathways of GPCRs.(Figure from


Structure of GPCRs


GPCRs are the largest family of human cell surface receptors. They contain a conserved structure of seven transmembrane domains. Their amino terminus is located extracellularly, whereas the carboxy terminus extends into the cytoplasm.

They are also called seven-pass transmembrane proteins because they cross the membrane seven times. The parts of the receptor that pass through the membrane are alpha helices. As would be expected, this transmembrane protein contains both hydrophobic and hydrophilic amino acids. The N-terminus is located on the extracellular side and the C-terminus of the protein is located on the cytosolic side of the membrane. Another feature that is common to most GPCRs is palmitoylation, which is the modification of cysteine residues with an acyl group. This modification targets GPCRs for cholesterol and sphingolipid-rich domains of the plasma membrane. These regions are known as lipid rafts[2,3].


Fig.2 The structure of GPCRs


Classification of GPCRs


According to the classical A-F system, GPCRs can be grouped into 6 classes based on sequence homology and functional similarity:

Class A (or 1) (Rhodopsin-like)

Class B (or 2) (Secretin receptor family)

Class C (or 3) (Metabotropic glutamate/pheromone)

Class D (or 4) (Fungal mating pheromone receptors)

Class E (or 5) (Cyclic AMP receptors)

Class F (or 6) (Frizzled/Smoothened)


The Role of GPCRs


GPCRs are involved in sight, taste, smell, behavioral, and mood regulation, and regulation of the immune system. Even though the signaling molecules, types of GPCR, and mechanisms of action may be different for all these roles, all of them involve certain extracellular signals that are converted into a cellular response. For example, mood regulation is affected by GPCRs because these receptors in the mammalian brain can bind to different neurotransmitters and create different physiological responses. Some of the molecules that can bind to GPCRs in the brain and lead to different moods are dopamine, serotonin, and GABA.



[1] King N, Hittinger CT, Carroll SB. The evolution of key cell signaling and adhesion protein families predates animal origins. Science. 2003 June; 301 (5631): 361–3.

[2] Park J, Selvam B, Sanematsu K, et al. Structural architecture of a dimeric class C GPCR based on co-trafficking of sweet taste receptor subunits. J Biol Chem. 2019 Mar 29; 294(13): 4759-4774.

[3] Kotula-Balak M, Pawlicki P, Milon A, et al. The role of G-protein-coupled membrane estrogen receptor in mouse Leydig cell function-in vivo and in vitro evaluation. Cell Tissue Res. 2018 Nov; 374(2): 389-412.

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