G Protein-Coupled Receptors Across Diverse Astrocyte Functions and Cellular Crosstalk

Astrocytes are the most abundant and functionally versatile glial cells in the central nervous system, where they maintain homeostasis, regulate metabolic function, and communicate extensively with neurons, microglia and other CNS cell types. To mediate these interactions, astrocytes use G-protein-coupled receptors (GPCRs) to receive diverse extracellular signals, such as neurotransmitters, secreted signals and inflammatory factors. GPCRs translate extracellular signals into intracellular signaling cascades in astrocytes and are essential for intercellular communication. Despite decades of investigation, however, astrocytic GPCR signaling remains difficult to explain within a unified framework, as receptor activation does not necessarily produce predictable outcomes based on receptor identity or G-protein signaling alone. To address this gap, we critically examine representative studies of canonical and noncanonical GPCR signaling and astrocyte-centered cellular crosstalk, considering astrocyte state and the cellular position of receptors within communication pathways. We compare receptor-specific manipulations, functional outcomes, and methodological limitations to distinguish experimentally supported causal relationships from unresolved interpretations. This evidence-oriented approach identifies testable questions and experimental priorities for investigating astrocytic GPCR signaling in physiology and disease.