GPCRs as key mediators of cell signalling and cell physiology

The human genome encodes around 800 transmembrane proteins with a conserved architecture containing seven hydrophobic transmembrane spanning regions. Most of these TM7 proteins can transmit intracellular signals via G proteins, hence the name G protein coupled receptors. GPCRs are the largest class of membrane receptors in human cells. Of the 800 known GPCRs, around 400 are involved in olfaction, 33 are taste receptors, 10 are involved in light perception and 5 are pheromone receptors. That leaves around 350 non-sensory GPCRs that mediate cell signalling including many aspects of endocrinology, cellular physiology and immunity (S. P. AlexanderChristopoulos et al. , 2021). The first classification scheme for GPCRs across all eukaryotes divided them into six different classes based on conserved structures (Kolakowski, 1994) and subsequent phylogenetic studies identified five broad families of human GPCRs; Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2 and Secretin comprising the GRAFS classification system (Schiƶth & Fredriksson, 2005). The Glutamate (Class C) family includes the metabotropic glutamate receptors, the GABAB receptors and three taste receptors. The Rhodopsin (Class A) receptor family responds to a wide variety of small molecules, neurotransmitters, peptides and hormones, including but not limited to dopamine, cannabinoids, opioids, chemokines and adenosine. The adhesion receptors (aGPCRs) are the second largest family of GPCRs with 33 human orthologues (Folts, Giera et al. , 2019). The aGPCRs have large extracellular N-termini that can be proteolytically cleaved leading to signalling. Mutations in aGPCRs have been shown to contribute to or increase susceptibility to human diseases including Usher Syndrome, attention deficit hyperactivity disorder and Tourette disorder. Recently mutations in ADGRE2/EMR2 have implicated EMR2 as a mechanoreceptor in mast cells and macrophages (Boyden, Desai et al. , 2016; I, Tsenget al. , 2020). The Frizzled family consists of 11 GPCRs and the Secretin family 15 GPCRs in the human genome. Secretin family receptors signal in response to polypeptide hormones including glucagon-like peptide-1.
The single copy gene encoding GPR84 is uninterrupted by introns and codes for 396 amino acid orthologues in both humans and mice (Wittenberger, Schaller et al. , 2001; Yousefi, Cooper et al. , 2001). On its discovery in 2001, prior to the deorphanisation of the FFARs, GPR84 could not be assigned a subfamily based on similarity to other known GPCRs (Wittenberger, Schaller et al. , 2001). Later, a phylogenetic tree analysis highlighted that GPR84 and FFAR4 bear only a distant evolutionary relationship with FFARs 1, 2 and 3 (Ichimura, Hirasawa et al. , 2009). In 2013 the IUPHAR noted there was insufficient evidence to classify GPR84 as FFAR5 (Davenport, Alexander et al. , 2013).
GPR84 is conserved across vertebrates dating back at least 400-550 Myr (Schulze 2022). A short 20 years on from its identification, a majority of the research on GPR84 has indicated that it has major roles in inflammation, given the receptor is highly expressed by immune cells, induced by inflammatory stimuli, and augments pro-inflammatory effector functions (Luscombe, Lucy et al. , 2020). Deletion of GPR84in mice does not lead to embryonic death or any obvious growth or fertility defect, suggesting that this GPCR does not play a non-redundant role in host physiology. It has been suggested to involve the host detection of bacterial quorum sensing molecules or metabolites from dying bacteria (Peters, Rabe et al. , 2020; Schulze, Kleinauet al. , 2022).