This post was originally published on here
Follow us on
Srinagar, Jan 02: In a significant advance in cell signaling research, Dr. Ajit Prakash, a Research Associate in the Sharon Campbell laboratory at the University of North Carolina at Chapel Hill, led a groundbreaking study uncovering how a key cellular signaling protein functions as an intracellular pH sensor.
The research has been published in the prestigious journal Nature Communications 2025. The study uncovers a previously unknown mechanism by which Gαi, a critical component of G-protein–coupled receptor (GPCR) signaling pathways, detects subtle changes in intracellular acidity and adjusts cellular signaling accordingly.
GPCRs represent the largest class of drug targets worldwide and regulate processes ranging from heart rate and metabolism to cancer progression and neurological function.
How pH Shapes Cellular Signaling
Cells tightly regulate their internal pH, but even small fluctuations occur during conditions such as cancer, ischemia, hypoxia, and metabolic stress.
Dr. Prakash and his team discovered that these pH changes directly influence the structure, stability, and activity of Gαi. Using advanced techniques including nuclear magnetic resonance (NMR) spectroscopy, biophysical assays, molecular dynamics simulations, and live-cell signaling experiments, the researchers showed that lower intracellular pH makes Gαi more flexible and disordered.
This altered state strengthens its interaction with partner proteins (Gβγ), effectively dampening downstream signaling. At higher physiological pH, Gαi becomes more stable, allowing proper signal transmission after receptor activation.
Discovery of a molecular pH-Sensing Switch
The team identified three critical amino acids within Gαi that form a pH-sensitive electrostatic network. These residues act as a molecular switch, enabling the protein to respond precisely to changes in proton concentration.
When these residues were mutated, Gαi behaved as if it were permanently in a low-pH environment, confirming their central role in pH sensing and signal regulation.
“This is the first time we’ve been able to explain, at the molecular level, how a heterotrimeric G protein senses intracellular pH and translates it into functional signaling outcomes,” said Dr. Prakash.
Implications for disease, drug discovery
The findings have broad implications for understanding diseases where cellular pH is disrupted, including cancer, neurological disorders, and cardiovascular disease.
Since GPCR signaling lies at the heart of modern pharmacology, this work opens new opportunities to design drugs that selectively target pH-dependent signaling states. Importantly, the study also suggests that similar pH-sensing mechanisms may exist in other G-protein subtypes, extending the impact of the discovery well beyond one isoform of protein.
Global recognition
Published in Nature Communications, one of the world’s leading multidisciplinary science journals, the work places Dr. Prakash among a growing group of scientists advancing fundamental insights into mechanisms of intracellular pH sensing.
The research was conducted in collaboration with scientists at UNC-Chapel Hill, combining structural biology, computational modeling, and live-cell signaling approaches to address a long-standing question in molecular pharmacology.
