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 C. elegans DEG/ENaC family using Two-Electrode Voltage Clamp (TEVC) in Xenopus oocytes. We found two groups of acidsensing DEG/ENaCs characterised by being 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 four new members of the acid-inhibited DEG/ENaC group, giving a total of seven additional acidsensitive 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 .

Functional analysis in a model sea anemone reveals phylogenetic complexity and a role in cnidocyte discharge of DEG/ENaC ion channels

“…C. elegans ACD-2 is a close relative of ACD-1, ACD-5, and FLR-1 (Fig. 1 ) and has recently been reported to be activated by protons with low sensitivity (pH 50 = 5.0) 55 . Belonging to the same clade is Drosophila PPK1, which is expressed in multidendritic sensory neurons, and has also been reported to sense acid 58 .…”

“…TadNaC2 is also activated by protons with low sensitivity (pH 50 = 5.1) 29 and TadNaC6 is a constitutively open channel which is modulated by alkaline pH 15 . While Del-9 is also activated by protons with low sensitivity (pH 50 = 4.3) 55 , the activating stimulus of Del-10 is currently unknown. It is therefore tempting to conclude that the last common ancestor of Cnidaria, Placozoa and deuterostomes had a proton-sensitive DEG/ENaC, which was at the base of this subclade, and that multiple duplication events occurred during the later evolution of these lineages, including independent gene losses in some protostomes and medusozoans.…”

The diverse functions of the DEG/ENaC family: linking genetic and physiological insights

“…The DEG/ENaC channels show a diversity in ion selectivity and permeability; while many are Na + -selective, some are also permeable to K + or Ca 2+ , and some invertebrate members exhibit a greater relative selectivity for other cations than Na + (Dürrnagel et al 2012;Fechner et al 2021;Kaulich et al 2022b;Wang et al 2008;further reviewed in Vallee et al 2021).…”

“…This includes vertebrate ASICs Coric et al 2005;Springauf & Grunder, 2010;Waldmann et al 1997b;Zhang & Canessa, 2002), likely Drosophila Ppk1 (Boiko et al 2012) (although this has not been confirmed by heterologous expression), C. elegans ASIC-1 and DEL-9 (Kaulich et al 2022b) and cnidarian, brachiopod, phoronid, annelid, xenacoelomorpha and hemichordate representatives (Aguilar-Camacho et al 2022;Martí-Solans et al 2022). The other subgroup of the acid-activated channels includes the human ENaCs (Collier & Snyder, 2009;Ji & Benos, 2004) and C. elegans ACD-2 (Kaulich et al 2022b), which show some basal activity that can be blocked by amiloride and enhanced by acidic extracellular pH. However, this may not necessarily infer basal activity in vivo, depending on the physiological pH environment that the channel encounters, and could also be because heterologous expression rarely reflects the physiological environment.…”

“…Amiloride inhibits a wide variety of DEG/ENaCs, with dramatic variation in potency (Boiko et al 2012;Canessa et al 1994;Garcia-Anoveros et al 1998;Goodman et al 2002;Han et al 2013;Waldmann et al 1997b;Wang et al 2008). Indeed, for some ASICs, it can enhance currents and even activate the channel (Adams et al 1999b;Kaulich et al 2022aKaulich et al , 2022bLi et al 2011b). ASICs are also targets of non-steroidal anti-inflammatory drugs (NSAIDs) (Voilley, 2004;Voilley et al 2001), a diverse group of chemicals used to treat pain and inflammation.…”