Exploring the diversity within acid sensors

Our neurons respond to cues from other neurons or from their environment by rapidly producing electrical signals. This responsiveness is possible thanks to ligand-gated ion channels, a very special group of proteins found on the surface of neurons that converts extracellular chemical stimuli (such as changes in the external pH) into intracellular electrical signals within milliseconds. Despite the importance of these proteins, their origin and how they were employed remain elusive.

Josep Martí-Solans, postdoctoral fellow in the Lynagh lab, explored this evolutionary question in collaboration with Aina Børve, an engineer in the group of Professor Andreas Hejnol, and PhD candidate Paul Bump from Stanford University. Their work, newly published in eLife, focuses on a protein family that plays a crucial role in the signaling happening in our brain and peripheral nervous system: the acid-sensing ion channels (ASICs). “I am interested in understanding how the function of proteins emerges during evolution”, Josep explains. “Here, we have characterized a lot of ASICs in a lot of organisms to get an idea of what these channels can do.”

By expanding the range of species for which these crucial neuronal proteins are known, the authors discovered that they were not specific to deuterostomes (e.g. sea urchins, fishes, and mammals) as previously thought. Their results suggest instead that ASICs first emerged in the first bilaterian animals – the ancestors of today’s flatworms, molluscs, flies, and humans – and probably served a role sensing the shifts in ambient pH rather than participating in neuron communication as ASICs do in today’s mammals.

“We have discovered many properties that were not thought to be feasible in nature”

Josep Martí-Solans

“We have found channels that are very sensitive to changes in the extracellular pH and others that tend to remain open for more time than most channels do when the ligand is bound”. These findings demonstrate that proteins with very similar amino-acid sequences can serve different physiological roles, a property that natural selection might exploit during evolution. By expanding the existing amino acid sequence data on proteins with acid-sensing and ion channel functions, the authors also aim to enable the characterization of the molecular mechanisms of these proteins.

For Josep, future work will involve the meticulous comparison of ASICs protein sequences through mutagenesis. “By expressing mutated ASICs on the surface of frog eggs, we are able to dissect the role of each amino acid”, he explains. This approach will allow the team to explore more in detail the evolution of the function of ligand-gated channels, identifying to the amino-acid level the mutations that make their role in today’s animals.