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.