Jean-Philippe Pin

G protein‐coupled receptors (GPCRs) constitute the largest family of drug targets, acting through heterotrimeric G proteins. Agonist bound GPCRs promote GDP release from G proteins allowing their activation upon GTP binding. Here, we analyze this process with innovative tools that detect the main states of native Gi proteins: the GDP‐bound, the open nucleotide‐free and the active GTP‐bound states. We show that receptor activation increases the amount of open‐state Gi proteins, consistent with GDP release from inactive Gi proteins. We also observe that the active receptor can release GTP from the active Gi protein, to return to an inactive open state. Consistently, receptor activation also promotes the formation of the Gαβγ complex from the GTP‐bound state in cells, in agreement with the formation of the receptor‐G protein ternary complex. These data suggest that the amount of active GTP‐bound form produced upon GPCR activation can be controlled by the receptor‐induced GTP release. This control of G protein state equilibrium that depends on the receptor subtype may affect coupling efficacy. These data reveal receptor‐dependent G‐protein state equilibria and identify GTP release as an additional, context‐dependent control point that can shape apparent coupling efficacy.

The class A orphan GPCRs have been organised into the subfamilies listed below, to better segregate them based on evidence (or lack of evidence) for endogenous ligand or surrogate ligand interactions, and potential for deorphanization. The Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR) published a review that included the evidence for potential deorphanisations in spring 2026 [12].

Immunotherapy is a promising avenue for reducing amyloid‐β (Aβ) accumulation, a hallmark of Alzheimer's disease (AD) pathology. Camelid single domain antibodies, called nanobodies, offer several advantages over conventional monoclonal antibodies, including improved brain penetration and fine‐tuning of the targeted neuroreceptors, and may represent an effective strategy to modulate Aβ production. Among potential therapeutic targets, group II metabotropic glutamate receptors (mGluR2 and mGluR3) have been implicated in Aβ regulation, though their individual contributions remain unclear. Here, we showed that activation of mGluR2 significantly increases Aβ peptides and sAPPβ production in a cellular model, by enhancing the internalization of amyloid precursor protein (APP) and its subsequent amyloidogenic processing. In contrast, mGluR3 directly interacts with APP, protecting it from amyloidogenic cleavage and favoring its non‐amyloidogenic processing. We used a brain‐penetrant nanobody acting as a selective positive allosteric modulator of mGluR2 to validate its role in Aβ dynamics in vivo. Chronic administration of this nanobody in 5xFAD mice accelerated amyloid plaque deposition and worsened cognitive deficits. These findings establish mGluR2 as a target in AD and demonstrate that its selective modulation by nanobodies influences Aβ pathology. This also highlights the potential of nanobodies as next‐generation therapeutic agents for modulating neuroreceptors activity in AD.

G protein coupled receptors (GPCRs) oligomerization may allow signal integration from different GPCR units. The GABA_B receptor, activated by the main inhibitory transmitter, GABA, is an obligatory heterodimer. It is the target of two therapeutic drugs, baclofen and GHB, and can form stable oligomers. The existence, roles, and possible allosteric interaction of GABA_B oligomers remain elusive. Here, we show that GABA_B oligomers exist in neurons. Their function can be specifically affected by human disease-associated mutations, demonstrating their essential role for normal brain function. The cryo-EM structure of a hetero-tetramer in the apo state reveals the heterodimers interacting in an asymmetrical way to prevent one unit from being activated. This represents a nice example of a negative allosteric interaction between GPCRs related to human diseases.

G protein-coupled receptor (GPCR) dimers and higher-order oligomers are the subject of intense debates. The complexes formed between two or more different GPCRs enable the cell to integrate several signals. But the mechanisms of the allosteric interaction within these oligomers remain unclear. Here, we use as a model the heteromer formed in the brain between two targets of anti-psychotic drugs, the metabotropic glutamate receptor 2 (mGlu2) and the serotonin receptor 5-HT_2A. Using molecular dynamics, a nanobody-based sensor and resonance energy transfer assays, we demonstrate that the 5-HT_2A receptor behaves as a positive allosteric modulator by stabilizing the active conformation of mGlu2. Using cysteine cross-linking experiments and mGlu2 sensors, we reveal the molecular basis for this allosteric modulation of the mGlu2 receptor by 5-HT_2A, an effect also mediated by other GPCRs. Our results thus provide insights into the allosteric control of a GPCR activity via heteromerization with another receptor.

The Concise Guide to Pharmacology 2025/26 marks the seventh edition in this series of biennial publications in the British Journal of Pharmacology. Presented in landscape format, the guide provides a comparative overview of the pharmacology of drug target families. The concise nature of the Concise Guide refers to the style of presentation, being clear, accessible, and well‐structured, rather than the scope of the content, which spans approximately 500 pages. The Concise Guide summarises the key pharmacological properties of around 1900 human drug targets, and nearly 7000 interactions, involving around 4400 ligands. While the content is a substantially condensed version of the more detailed information and links available at the www.guidetopharmacology.org website, the printed guide serves as a permanent, citable, point‐in‐time record, that remains stable despite ongoing updates to the online database. The full contents of this publication can be found at https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.70230 . The Concise Guides provide expert‐curated recommendations of ‘Gold Standard’ selective pharmacological tools, available either commercially or as donations, which enable the identification of individual drug targets or families of drug targets. While the Concise Guide offers a more streamlined overview, more comprehensive information, including detailed pharmacological profiles and links to multiple online databases, is available through the Guide to Pharmacology website. The 2025/26 edition of the Concise Guide is based on material current as of mid‐2025, and supersedes all previous editions, including the 2023/24 Guide, and earlier Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), and as such provides official IUPHAR classification and nomenclature for human drug targets, where applicable. G protein‐coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. Each section includes nomenclature guidance, concise summaries, information of the best available pharmacological tools, key references, and suggestions for further reading.

The internalization of G protein-coupled receptors (GPCRs) is a key process limiting cell surface receptor activity, and possibly promoting their intracellular signaling. Dysregulation of this process has been implicated in various diseases. This process is known to result from the recruitment of β-arrestins (βarrs) to the active receptors, although some receptors do not require this for unclear reasons. Here, we clarify the importance of βarrs in the internalization of 60 different GPCRs. We show that βarrs are essential for agonist-induced internalization for only a third of the receptors, half of the GPCRs being partially dependent on βarrs or even independent for endocytosis. Furthermore, we develop several Förster resonance energy transfer (FRET)-based molecular interaction assays to elucidate the molecular mechanism of internalization of the glucagon-like peptide-1 receptor (GLP-1R). We show that GLP-1R internalizes mainly by a βarr-independent mechanism involving the direct binding of the clathrin adaptor protein complex-2 to the receptor. However, when this adaptor protein complex-2-dependent mechanism is affected, the GLP-1R internalization becomes βarr-dependent. It shows that multiple mechanisms regulate the internalization of a specific receptor. Our data highlight the various processes used to control cell surface GPCRs, and open novel possibilities to specifically control their signaling processes.

The class A orphan GPCRs have been organised into the subfamilies listed below, to better segregate them based on evidence (or lack of evidence) for endogenous ligand or surrogate ligand interactions, and potential for deorphanization.

Table 1 lists a number of putative GPCRs identified by NC-IUPHAR [206], for which preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to a disease, or disorder. These GPCRs have recently been reviewed in detail [156]. The GPCRs in Table 1 are all Class A, rhodopsin-like GPCRs. Class A orphan GPCRs not listed in Table 1 are putative GPCRs with as-yet unidentified endogenous ligands.Table 1: Class A orphan GPCRs with putative endogenous ligands GPR3GPR4GPR6GPR12GPR15GPR17GPR20 GPR22GPR26GPR31GPR34GPR35GPR37GPR39 GPR50GPR63GPR65GPR68GPR75GPR84GPR87 GPR88GPR132GPR149GPR161GPR183LGR4LGR5 LGR6MAS1MRGPRDMRGPRX1MRGPRX2P2RY10TAAR2 In addition the orphan receptors GPR18, GPR55 and GPR119 which are reported to respond to endogenous agents analogous to the endogenous cannabinoid ligands have been grouped together (GPR18, GPR55 and GPR119).