G Protein-Coupled Receptor Signaling Cascade

G protein-coupled receptors (GPCRs) are seven-transmembrane proteins expressed in virtually every human cell. GPCRs are activated by extracellular endogenous and exogenous ligands including ions, small molecules, neurotransmitters, peptides, proteins, and other sensory inputs. The binding of an agonist (a peptide displayed here in green) causes conformational changes in the GPCR (Rasmussen et al., 2011) (1) leading to activation and coupling to membrane-anchored heterotrimeric G proteins. Exchange of GDP to GTP leads (2) to Gα (brown) and Gβγ (red and cyan, respectively) subunit dissociation, which independently activates further downstream signaling by second messengers such as cAMP, IP_1/3 and Ca²⁺ (3) (Senarath et al., 2018). The Gαβγ heterotrimer is then reassembled after hydrolysis of GTP to GDP. GPCR kinases phosphorylate the activated receptor and, thus, recruit arrestins (4) promoting desensitization and internalization, which leads to downregulation of receptor activity within minutes or hours (Smith et al., 2018). Arrestins can further trigger additional signaling pathways (Gurevich & Gurevich, 2019).

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Gurevich, V. V., & Gurevich, E. V. (2019). GPCR Signaling Regulation: The Role of GRKs and Arrestins. Frontiers in Pharmacology, 10, 125. https://doi.org/10.3389/fphar.2019.00125

Rasmussen, S. G. F., DeVree, B. T., Zou, Y., Kruse, A. C., Chung, K. Y., Kobilka, T. S., Thian, F. S., Chae, P. S., Pardon, E., Calinski, D., Mathiesen, J. M., Shah, S. T. A., Lyons, J. A., Caffrey, M., Gellman, S. H., Steyaert, J., Skiniotis, G., Weis, W. I., Sunahara, R. K., & Kobilka, B. K. (2011). Crystal structure of the β2 adrenergic receptor-Gs protein complex. Nature, 477(7366), 549–555. https://doi.org/10.1038/nature10361

Senarath, K., Kankanamge, D., Samaradivakara, S., Ratnayake, K., Tennakoon, M., & Karunarathne, A. (2018). Regulation of G Protein βγ Signaling. International Review of Cell and Molecular Biology, 339, 133–191. https://doi.org/10.1016/BS.IRCMB.2018.02.008

Smith, J. S., Lefkowitz, R. J., & Rajagopal, S. (2018). Biased signalling: from simple switches to allosteric microprocessors. Nature Reviews Drug Discovery, 17(4), 243–260. https://doi.org/10.1038/nrd.2017.229