Physiological insight into the conserved properties of Caenorhabditis elegans acid‐sensing degenerin/epithelial sodium channels

ABSTRACT: Acid‐sensing ion channels (ASICs) are members of the diverse family of degenerin/epithelial sodium channels (DEG/ENaCs). They perform a wide range of physiological roles in healthy organisms, including in gut function and synaptic transmission, but also play important roles in disease, as acidosis is a hallmark of painful inflammatory and ischaemic conditions. We performed a screen for acid sensitivity on all 30 subunits of the Caenorhabditis elegans DEG/ENaC family using two‐electrode voltage clamp in Xenopus oocytes. We found two groups of acid‐sensitive DEG/ENaCs characterised by being either inhibited or activated by increasing proton concentrations. Three of these acid‐sensitive C. elegans DEG/ENaCs were activated by acidic pH, making them functionally similar to the vertebrate ASICs. We also identified three new members of the acid‐inhibited DEG/ENaC group, giving a total of seven additional acid‐sensitive channels. We observed sensitivity to the anti‐hypertensive drug amiloride as well as modulation by the trace element zinc. Acid‐sensitive DEG/ENaCs were found to be expressed in both neurons and non‐neuronal tissue, highlighting the likely functional diversity of these channels. Our findings provide a framework to exploit the C. elegans channels as models to study the function of these acid‐sensing channels in vivo, as well as to study them as potential targets for anti‐helminthic drugs. [Image: see text] KEY POINTS: Acidosis plays many roles in healthy physiology, including synaptic transmission and gut function, but is also a key feature of inflammatory pain, ischaemia and many other conditions. Cells monitor acidosis of their surroundings via pH‐sensing channels, including the acid‐sensing ion channels (ASICs). These are members of the degenerin/epithelial sodium channel (DEG/ENaC) family, along with, as the name suggests, vertebrate ENaCs and degenerins of the roundworm Caenorhabditis elegans. By screening all 30 C. elegans DEG/ENaCs for pH dependence, we describe, for the first time, three acid‐activated members, as well as three additional acid‐inhibited channels. We surveyed both groups for sensitivity to amiloride and zinc; like their mammalian counterparts, their currents can be blocked, enhanced or unaffected by these modulators. Likewise, they exhibit diverse ion selectivity. Our findings underline the diversity of acid‐sensitive DEG/ENaCs across species and provide a comparative resource for better understanding the molecular basis of their function.