G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors and central mediators of endocrine communication, governing hormone sensing, secretion, and downstream physiological responses. For decades, the prevailing model placed GPCR signaling at the plasma membrane, terminated by receptor internalization. That view has been fundamentally revised. GPCRs are now known to signal from endosomes, the Golgi apparatus, the nuclear envelope, and other intracellular compartments, generating sustained and spatially distinct responses that shape the specificity and duration of endocrine signaling. Alongside this compartmentalization, the concepts of biased and location-biased signaling -and of non-canonical mechanisms operating beyond classical G protein coupling- have reshaped our understanding of how a single receptor can produce diverse, context-dependent outcomes.
Despite rapid progress, evidence on non-canonical and intracellular GPCR signaling remains dispersed across receptor families, cell types, and methodological approaches, and its integration into endocrine physiology is still incomplete. Bringing these threads together is essential to understand how spatially and mechanistically distinct GPCR signals are decoded into coordinated endocrine function, and to reveal new therapeutic opportunities in receptors that have long been considered undruggable through conventional strategies.
This Research Topic aims to consolidate mechanistic, structural, quantitative, and translational research on GPCR signaling that occurs beyond the plasma membrane and beyond canonical G protein pathways, with a focus on its relevance to endocrine function. We welcome Original Research, Reviews, Mini Reviews, Methods, Hypothesis and Theory, and Perspective articles. Themes of interest include, but are not limited to:
• Endosomal and sustained signaling: receptor trafficking, compartmentalized second-messenger generation, and the temporal control of endocrine responses
• Nuclear and nuclear-envelope GPCRs: localization, activation, and transcriptional or non-transcriptional roles in endocrine cells
• Signaling from the Golgi and other intracellular compartments: organelle-specific GPCR activity and its functional consequences
• Biased signaling, location-biased signaling, and location-biased activity: how ligand- and compartment-dependent bias shapes endocrine outcomes
• Non-canonical mechanisms beyond G protein–mediated signaling: arrestin-dependent, transactivation, and other unconventional pathways
• Structural, quantitative, and methodological advances enabling the study of compartmentalized and non-canonical GPCR signaling
• Translational and therapeutic perspectives targeting intracellular or biased GPCR signaling in endocrine disorders
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Article types
This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:
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