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).