FIGURES
Figure 1 GPCR signalling and pharmacology
A ) GPCR are composed of seven transmembrane domains connecting
the extracellular domain [N-terminus, extracellular loops (EL) 1-3]
where various ligands bind the receptor (e.g., natural ligands
and chemicals/antibodies), to the intracellular domain [intracellular
loops (IL) 1-3, helix H8, C-terminus] that recruit the direct
transducers, which activate a signalling network (e.g., Akt, ERK)
and integrated cellular processes. A biased ligand has the particular
pharmacological profile to favour signalling pathways within the complex
receptor signalling network. Here, a G protein-biased ligand that
favours G protein coupling (black arrow) over β-arrestin recruitment
(grey arrow) is shown. The radial graph represents the maximum efficacy
(Emax) of this G protein-biased ligand to stimulate the indicated
signalling responses. The scale is indicated as % of the efficacy of
the natural ligand. B ) GPCRs display a rich pharmacopoeia of
ligands, with agonists, antagonists and inverse agonists that bind to
the orthosteric binding site (e.g., the binding site of the natural
ligand) to respectively activate or prevent the agonist binding and
inactivate the receptor. Other ligands bind to allosteric sites that
increase or decrease the efficacy or efficiency of the natural ligand,
respectively called positive or negative allosteric modulators.
Figure 2 At least 15% of SFARI genes participate in
GPCR activity and signalling processes
GPCR ligands are synthesized by metabolic enzymes, loaded by their
transporters into synaptic vesicles that fuse with the presynaptic
membrane upon increase of intracellular calcium, leading to
neurotransmitter release in the synaptic cleft. These neurotransmitters
or ligands are either recaptured by membrane transporters, degraded, or
bind and activate their cognate GPCR. Even in the absence of ligand,
GPCRs are present in preformed higher complexes with scaffolding
partners, channels, cytoskeleton and signalling transducers. Upon GPCR
activation, transducers activate enzyme and channel effectors to produce
second messengers. These second messengers activate major kinases and
guanine nucleotide exchange factor (GEF) that tune up or down downstream
cellular processes, including translation and transcription. Syndromic
(in red), high confidence (category 1 in dark orange), strong candidate
(category 2 in light orange) and suggestive evidence (category 3 in
green) genes are coloured according to SFARI gene scoring and colour
code (gene.sfari.org/about-gene-scoring, Table S1 ) and
additional GPCR genes are in black. GPCRs are localized at pre,
post-synaptic compartment of neurons, in astrocytes or in unknown or
other cell types according to their expression pattern (see text for
further details).
Figure 3 GPCR localisation and expression in the human
and mouse brain
Relative expression and localisation of the 25 GPCRs are presented on
the murine and human brain templates from the protein atlas database
(www.proteinatlas.org). After comparison to protein expression for
consistency (only available for the 5-HT1B,
5-HT2A, 5-HT7, A2A,
V1B, M3, CB1,
CX3CR1, D2, GABAB2 and
GPR37), relative RNA levels are represented as high (brown, over 20
normalised transcript expression values, expressed as nTPM), moderate
(red, 10-20 nTPM), low (pink, 2-10 nTPM) and just detectable (light
pink, 0.1-2 nTPM) expression in the CNS (expression in the other organs
are indicated in Table S4 and S6 ). Brain templates are from
Servier Medical Art.