2026-02-10
GPCRs: thinking beyond the membrane
Medical Biology
By Ana Espino | Published on February 9, 2026 | 3 min read
G protein-coupled receptors (GPCRs) are central to cellular signaling. They regulate key physiological functions—cardiovascular, neurological, immune—and account for nearly one-third of all current drug targets. Traditionally, GPCRs were thought to function exclusively at the plasma membrane, where they initiate rapid and transient intracellular signaling via G proteins and β-arrestins.
However, this classical view is now showing its limits. Growing evidence reveals that GPCRs can also signal from intracellular compartments such as the endosomes, the Golgi apparatus, and even the nucleus, producing distinct and often prolonged effects. Traditional pharmacological tools lack the spatial resolution to differentiate these signals based on their subcellular origin, limiting our ability to design specific, localized, and more effective drugs.
In response, an emerging therapeutic approach involves using chemical biology tools to visualize, modulate, and decode GPCR signaling within intracellular compartments. This strategy offers a unique opportunity to create a dynamic and compartmentalized map of signaling pathways.
This study was therefore initiated to review recent chemical biology-based approaches that help unravel intracellular GPCR signaling, and to assess their potential for transforming targeted pharmacology.
This review highlights the use of compartment-targeted chemical probes that can activate or inhibit GPCRs in specific locations such as endosomes or the Golgi apparatus. It also presents optogenetic and chemogenetic tools that enable spatiotemporal control of GPCR activation. Additionally, intracellular FRET/BRET biosensors are discussed, designed to detect G protein or β-arrestin activation in defined subcellular regions, along with molecular targeting platforms that use localization signals to redirect receptors or their effectors to specific compartments.
The evidence confirms that GPCRs are not limited to plasma membrane signaling. Distinct signals also arise from endosomes, the Golgi, and occasionally non-conventional organelles, influencing the duration, intensity, and quality of cellular responses. This intracellular signaling landscape could explain the differential effects observed with certain ligands, and paves the way for the development of more precise, spatially targeted, and functionally selective therapeutics.
GPCRs are critical pharmacological targets, yet their intracellular signaling remains largely unexplored. The main current challenge lies in the inability of conventional tools to distinguish signals based on subcellular origin, which limits the precision of targeted therapies. This review aimed to shed light on recently developed chemical biology tools that allow for the analysis and modulation of GPCR signaling within specific cellular compartments. It demonstrates that the subcellular localization of a receptor profoundly influences the nature, duration, and strength of its signaling, opening new avenues for more refined and personalized pharmacological strategies.
However, limitations remain and further research is warranted. These future directions will include refining subcellular targeting tools, integrating dynamic data into more complex cellular models, and conducting in vivo functional studies to evaluate the physiopathological consequences of compartmentalized signaling. It will also be essential to better link these localized signals to whole-cell pharmacological responses, to ultimately develop drugs that act precisely where the signal truly originates.
About the author – Ana Espino
PhD in Immunology, specialized in Virology
As a scientific writer, Ana is passionate about bridging the gap between research and real-world impact. With expertise in immunology, virology, oncology, and clinical studies, she makes complex science clear and accessible. Her mission: to accelerate knowledge sharing and empower evidence-based decisions through impactful communication.
G protein-coupled receptors (GPCRs) are central to cellular signaling. They regulate key physiological functions—cardiovascular, neurological, immune—and account for nearly one-third of all current drug targets. Traditionally, GPCRs were thought to function exclusively at the plasma membrane, where they initiate rapid and transient intracellular signaling via G proteins and β-arrestins.
However, this classical view is now showing its limits. Growing evidence reveals that GPCRs can also signal from intracellular compartments such as the endosomes, the Golgi apparatus, and even the nucleus, producing distinct and often prolonged effects. Traditional pharmacological tools lack the spatial resolution to differentiate these signals based on their subcellular origin, limiting our ability to design specific, localized, and more effective drugs.
In response, an emerging therapeutic approach involves using chemical biology tools to visualize, modulate, and decode GPCR signaling within intracellular compartments. This strategy offers a unique opportunity to create a dynamic and compartmentalized map of signaling pathways.
This study was therefore initiated to review recent chemical biology-based approaches that help unravel intracellular GPCR signaling, and to assess their potential for transforming targeted pharmacology.
Can we trace intracellular signals?
This review highlights the use of compartment-targeted chemical probes that can activate or inhibit GPCRs in specific locations such as endosomes or the Golgi apparatus. It also presents optogenetic and chemogenetic tools that enable spatiotemporal control of GPCR activation. Additionally, intracellular FRET/BRET biosensors are discussed, designed to detect G protein or β-arrestin activation in defined subcellular regions, along with molecular targeting platforms that use localization signals to redirect receptors or their effectors to specific compartments.
The evidence confirms that GPCRs are not limited to plasma membrane signaling. Distinct signals also arise from endosomes, the Golgi, and occasionally non-conventional organelles, influencing the duration, intensity, and quality of cellular responses. This intracellular signaling landscape could explain the differential effects observed with certain ligands, and paves the way for the development of more precise, spatially targeted, and functionally selective therapeutics.
Toward 3D pharmacology?
GPCRs are critical pharmacological targets, yet their intracellular signaling remains largely unexplored. The main current challenge lies in the inability of conventional tools to distinguish signals based on subcellular origin, which limits the precision of targeted therapies. This review aimed to shed light on recently developed chemical biology tools that allow for the analysis and modulation of GPCR signaling within specific cellular compartments. It demonstrates that the subcellular localization of a receptor profoundly influences the nature, duration, and strength of its signaling, opening new avenues for more refined and personalized pharmacological strategies.
However, limitations remain and further research is warranted. These future directions will include refining subcellular targeting tools, integrating dynamic data into more complex cellular models, and conducting in vivo functional studies to evaluate the physiopathological consequences of compartmentalized signaling. It will also be essential to better link these localized signals to whole-cell pharmacological responses, to ultimately develop drugs that act precisely where the signal truly originates.
About the author – Ana Espino
PhD in Immunology, specialized in Virology
As a scientific writer, Ana is passionate about bridging the gap between research and real-world impact. With expertise in immunology, virology, oncology, and clinical studies, she makes complex science clear and accessible. Her mission: to accelerate knowledge sharing and empower evidence-based decisions through impactful communication.
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