A team of researchers has made significant strides in understanding how certain cellular receptors detect and respond to changes in acidity, including cell signaling, growth, and immune responses.
The study, focuses on a class of proteins known as pH-sensing G protein-coupled receptors (GPCRs), particularly GPR4 and its evolutionary relative GPR65. These receptors play a central role in detecting shifts in extracellular proton concentrations and triggering appropriate cellular responses.
Using cryo-electron microscopy, the team captured high-resolution structural images of GPR4 and GPR65 in various activation states and at different pH levels. These snapshots provide a detailed look at how the receptors change shape as the acidity around them shifts. Importantly, the researchers identified specific amino acids that form a network to facilitate proton detection.
One of the study’s key findings was the capture of intermediate activation states in GPR4, offering a rare glimpse into the step-by-step process of receptor activation. Additionally, they discovered a previously unknown binding site for a small molecule, NE52-QQ57, which appears to lock the receptor in an inactive state. This may offer a new path forward for drug development targeting diseases where pH sensing is disrupted, such as inflammation or cancer.
Beyond mapping the receptors’ external features, the research also examined how they interact internally with different G proteins. By comparing structures of GPR4 bound to different G proteins (Gs, Gq, and G13), the study revealed how subtle shifts in the receptors’ structure determine which signaling pathways are activated.
The complete study is available open access in Nature Cell Research.