GPCR-Mediated Cell Intelligence, a Critical Function for Survival and Long-Term Health

The concept of individual cellular intelligence reframes cells as dynamic entities endowed with sensory, reactive, adaptive, and memory-like capabilities, enabling them to navigate lifelong metabolic and extrinsic stressors. A likely vital component of this intelligence system are stress-responsive G protein-coupled receptor (GPCR) networks, interconnected by common signaling adaptors. These stress-regulating networks orchestrate the detection, processing, and experience retention of environmental cues, events, and stressors. These networks, along with other sensory mechanisms such as receptor-mediated signaling and DNA damage detection, allow cells to acknowledge and interpret stressors such as oxidative stress or nutrient scarcity. Reactive responses, including autophagy and apoptosis, mitigate immediate damage, while adaptive strategies, such as metabolic rewiring, receptor expression alteration and epigenetic modifications, enhance long-term survival. Cellular experiences that are effectively translated into ‘memories’, both transient and heritable, likely relies on GPCR-induced epigenetic and mitochondrial adaptations, enabling anticipation of future insults. Dysregulation of these processes and networks can drive pathological states, shaping resilience or susceptibility to chronic diseases like cancer, neurodegeneration, and metabolic disorders. Employing molecular evidence, here we underscore the presence of an effective cellular intelligence, supported by multi-level sensory GPCR networks. The quality of this intelligence acts as a critical determinant of somatic health and a promising frontier for therapeutic innovation. Future research leveraging single-cell omics and systems biology may unravel the molecular underpinnings of these capabilities, offering new strategies to prevent or reverse stress-induced pathologies.