Nilsson, K. A. | bioRxiv Science

bioRxiv2025

Profiling of HCAR1 signaling reveals Gαi/o and Gαs activation without β-arrestin recruitment and the discovery of an allosteric agonist

Lactate was long considered a byproduct of glycolysis and associated with various harmful effects. However, the role of lactate was expanded with the finding that it also can act as a signaling molecule through the G protein-coupled receptor Hydroxycarboxylic Acid Receptor 1 (HCAR1). The receptor was shown to be primarily expressed in adipocytes but is also expressed in many other tissues and cell types. Activation of HCAR1 can help regulate lipolysis and improve insulin sensitivity, making it a promising target for managing obesity and other metabolic disorders. While HCAR1 activation offers therapeutic benefits for metabolic diseases, it can also promote cancer cell survival and metastasis, necessitating a nuanced approach to avoid unintended tumor growth. However, only a few ligands have been reported for HCAR1, and their signaling pathways remain unexplored. Using enhanced bystander bioluminescence resonance energy transfer (ebBRET) to study G protein activation and {beta}-arrestin recruitment following ligand addition, we were able to identify compounds such as AZ7136, a potent HCAR1 agonist, AZ2114 a partial agonist, and establish GPR81 agonist 1 as an ago-positive allosteric modulator. We also show that HCAR1 preferentially activates the Gi/o and Gs pathways without recruiting {beta}-arrestins. These findings enhance our understanding of the signaling profile of HCAR1 and the newly characterized ligands could be used as molecular tools to understand more about HCAR1 in metabolic disease. One Sentence SummaryThis study used the ebBRET platform to identify and characterize several synthetic ligands for the lactate receptor HCAR1, significantly advancing our understanding of HCAR1 signaling.

pharmacology and toxicology↗

bioRxiv2019

Ecological speciation in European whitefish is driven by a large-gaped predator

Lake-dwelling fish that form species pairs/flocks characterized by body size divergence are important model systems for speciation research. While several sources of divergent selection have been identified in these systems, their importance for driving the speciation process remains elusive. A major problem is that in retrospect, we cannot distinguish selection pressures that initiated divergence from those acting later in the process. To address this issue, we reconstructed the initial stages of speciation in European whitefish (Coregonus lavaretus) using data from 357 populations of varying age (26-10 000 years). We find that whitefish speciation is driven by a large-growing predator, the northern pike (Esox lucius). Pike initiates divergence by causing a largely plastic differentiation into benthic giants and pelagic dwarfs; ecotypes that will subsequently develop partial reproductive isolation and heritable differences in gill raker number. Using an eco-evolutionary model, we demonstrate how pikes habitat specificity and large gape size are critical for imposing a between-habitat trade-off, causing prey to mature in a safer place or at a safer size. Thereby, we propose a novel mechanism for how predators may cause dwarf/giant speciation in lake-dwelling fish species.

evolutionary biology↗