Biology subjects

Jugnarain, V.

Publications and source records attributed to Jugnarain, V..

4 recordsLinked to original sources

bioRxiv2026

Spatiotemporal Modeling of GPCR Signaling: The Role of Endosomal Dynamics and Receptor Recycling

Cells communicate via extracellular ligands, such as hormones, which bind to plasma membrane receptors and trigger intracellular signaling cascades. G Protein-Coupled Receptors (GPCRs) exemplify this mechanism by initiating signaling both at the cell surface and, from intracellular compartments such as endosomes. The kinetics and spatial localization of these signals are critical determinants of cellular responses, yet receptor trafficking-including internalization, endosomal sorting, and recycling-remains a pivotal but often overlooked component of theoretical GPCR models. In this study, we present a mathematical framework that integrates receptor trafficking and signaling compartmentalization into generic GPCR dynamic models. Using a compartmentalized approach based on systems of ordinary differential equations (Chemical Reaction Networks), we analyze how receptor internalization and recycling modulate ligand-induced responses. Our results show that the balance between plasma membrane and endosomal signaling can significantly enhance or diminish ligand efficacy. Calibrated with high-throughput kinetic data, our model offers a refined tool for ligand pharmacological characterization and advances the understanding of GPCR signaling spatial organization.

systems biology↗

bioRxiv2025

LHR and Gαs trafficking drive sustained cAMP signalling from endosomes to control steroidogenesis

1.A growing number of G protein-coupled receptors (GPCRs) signal through G proteins from intracellular compartments following endocytosis. While for few receptors the physiological relevance of such mechanism has been established, the relationships between the spatio-temporal organization of cellular signalling and the physiological responses are still to be elucidated for most receptors. Signalling by the luteinizing hormone receptor (LHR) is essential to regulate sex steroids production in gonads, but how G protein-dependent signals from endosomes are functionally important for steroidogenesis remains unexplored. Here, we demonstrate that transient LHR activation promotes a prolonged Gs/cAMP signalling from endosomes, which requires ligand-induced independent receptor and Gs trafficking. We show that endosomal trafficking is specifically required for ligand-induced cAMP accumulation in the nucleus and gene expression, as well as for steroids production in Leydig cells. Thus, this study contributes to further understand the molecular mechanisms by which LHR, through signalling compartmentalization, controls gonadal steroidogenesis.

cell biology↗

bioRxiv2025

A single domain intrabody as a novel tool to bias the subcellular trafficking of the follicle-stimulating hormone receptor

Intracellular variable fragments from heavy-chain only antibodies of camelids (intra-VHH) have been successfully used for their stabilizing properties to solve the 3D structure of active G protein-coupled receptors (GPCRs) bound to their cognate transducers. They also provide tools to link a given conformation of a GPCR to the signalling network engaged, thus allowing extensive structure/activity studies. Recently, they have been instrumental in tracking active GPCRs in various subcellular compartments. Here, we report the isolation and characterization of iPRC2, an intra-VHH recognizing the 1st and 3rd intracellular loops of the FSHR, but not of the luteinizing hormone/choriogonadotropin receptor close relative. Its expression in the cell decreases the cAMP production in response to hormone binding, and requires Gs for optimal interaction with the receptor. Importantly, iPRC2 increases the FSHR accumulation in the early endosomes, and consequently, diminishes its recycling to the cell surface. Hence, in contrast to previously described intra-VHH that disclose active GPCR intracellular location, iPRC2 provokes per se a location bias, through its ability to reroute the FSHR. Thus, it is an innovative tool to examine the functional consequences of GPCR accumulation in various sub-cellular compartments.

pharmacology and toxicology↗

bioRxiv2023

A single domain intrabody targeting the follicle-stimulating hormone receptor (FSHR) impacts FSH-induced G protein-dependent signalling

Intracellular variable fragments from heavy-chain antibody from camelids (intra-VHH) have been successfully used as chaperones to solve the 3D structure of active G protein-coupled receptors bound to their transducers. However, their effect on signalling has been poorly explored, although they may provide a better understanding on the relationships between receptor conformation and activity. Here, we isolated and characterized iPRC1, the first intra-VHH recognizing a member of the large glycoprotein hormone receptors family, the follicle-stimulating hormone receptor (FSHR). This intra-VHH recognizes the FSHR 3rd intracellular loop and decreases cAMP production in response to FSH, without altering Gs recruitment. Hence, iPRC1 behaves as an allosteric modulator and provides a new tool to complete structure/activity studies performed so far on this receptor.

pharmacology and toxicology↗