G-protein coupled receptors (GPCRs)

For many years, it was believed that G-protein coupled receptors (GPCRs) signaled solely at the plasma membrane. However, research conducted over the past 15 years has uncovered that these receptors also engage in signaling through classical G-protein-mediated pathways on the membranes of intracellular organelles, including endosomes and the Golgi complex.
Calebiro et al. 2025 Trends in Biochemical Sciences 50(1): 46

The Thyrotropin receptor, Parathyroid hormone receptor (PTHR) and Beta-2 adrenergic receptor are three examples
Calebiro et al. 2025 Trends in Biochemical Sciences 50(1): 46

Endomembrane signaling plays a role in the impact of ligands released outside the cell, like hormones and neurotransmitters, which function in endocrine, paracrine, or autocrine ways. Furthermore, G protein-coupled receptors (GPCRs) located within the cell may act as detectors for metabolites produced locally, functioning in what is known as an 'intracrine' manner.
Calebiro et al. 2025 Trends in Biochemical Sciences 50(1): 46

The signaling of G-protein coupled receptors (GPCRs) relies on their interaction with heterotrimeric G proteins, which consist of alfa-, beta-, and gamma-subunits and are categorized into four alfa subunit types: Gαi, Gα12/13, Gαq, and Gαs.
Hu et al. 2024a Expert Opinion on Therapeutic Targets 28(10): 825-828

G-protein coupled receptors (GPCRs) are receptors for sugars, proteins, lipids, and peptides, causing cells to open ion channels, secrete substances, and regulate gene expression at the transcriptional level
Leurs et al. 2005 Nat Rev Drug Discov 4(2): 107-120

When an agonist binds to a G-protein coupled receptor (GPCR), a series of structural changes occur that lead to receptor activation. The active receptor then interacts with and activates heterotrimeric G proteins composed of alfa, beta, and gamma subunits
Calebiro et al. 2021 Physiol Rev 101: 857-906

G-protein coupled receptors (GPCRs) interact with a Guanine nucleotide-binding coupling proteins (G-proteins), from which their name is derived.
Geisslinger et al. 2020 Wissenschaftliche Verlagsgesellschaft mbH ISBN 978-3-8047-3663-4

G-protein coupled receptors (GPCRs) are a significant group of Receptors (membrane-bound). With about 800 genes, they not only represent the largest group within this family but also stand out due to their high diversity. These receptors are responsible for transmitting information from various extracellular stimuli to the cell interior.
Geisslinger et al. 2020 Wissenschaftliche Verlagsgesellschaft mbH ISBN 978-3-8047-3663-4

Due to similarities in their primary sequence, G-protein coupled receptors (GPCRs) can be divided into different subfamilies. One of the largest subfamilies is the Class A (Rhodopsin-like receptors), which includes, for example, the Adrenergic receptors (i.e., Alfa receptors and Beta receptors). These account for about 85% of all receptor genes.
Geisslinger et al. 2020 Wissenschaftliche Verlagsgesellschaft mbH ISBN 978-3-8047-3663-4

It is estimated that about 35% of all approved drugs exert their effects through G-protein coupled receptors (GPCRs). Thus, they are the largest pharmacologically relevant receptor family. Excluding the receptors for vision, smell, and taste, about 360 receptors remain. For about 100 of these receptors, the physiological, endogenous ligands are still unknown. These so-called orphan receptors represent potentially new pharmacological targets.
Geisslinger et al. 2020 Wissenschaftliche Verlagsgesellschaft mbH ISBN 978-3-8047-3663-4

Both the alfa and beta/gammaγ subunits, in turn, modulate the activity of enzymes such as Adenylyl cyclase or Phospholipase C (PLC) Beta, as well as ion channels. These events typically trigger the formation of second messengers and the activation of downstream signaling cascades that ultimately lead to specific biological responses
Pierce et al. 2002 Nat Rev Mol Cell Biol 3: 639-650
Lefkowitz 2004 Trends Pharmacol Sci 25: 413-422

When G-protein coupled receptors (GPCRs) signaling is persistently stimulated, it quickly becomes desensitized. This rapid desensitization is facilitated by G-protein-coupled receptor kinases (GRKs). These kinases phosphorylate serine and threonine residues, usually located in the receptors' C terminus or third intracellular loop.
Stadel et al. 1983 Proc Natl Acad Sci USA 80: 3173-3177
Pitcher et al. 1992 Biochemistry 31: 3193–3197
Pitcher et al. 1998 Annu Rev Biochem 67: 653-692
Krupnick & Benovic 1998 Annu Rev Pharmacol Toxicol 38: 289-319

see also:
Arrestins