Neuropeptides and degenerin/epithelial Na⁺ channels: a relationship from mammals to cnidarians

Abstract

Ion channels of the degenerin (DEG)/epithelial Na+ channel (ENaC) family serve diverse functions ranging from mechanosensation over Na+ reabsorption to H+ sensing and neurotransmission. However, several diverse DEG/ENaCs interact with neuropeptides; some are directly activated, whereas others are modulated by neuropeptides. Two questions arise: does this interaction have a common structural basis and does it have an ancient origin? Current evidence suggests that RFamide neuropeptides activate the FMRFamide‐activated Na+ channels (FaNaCs) of invertebrates via binding to a pocket at the external face of their large extracellular domain. It is likely that RFamides might activate DEG/ENaCs from the freshwater polyp Hydra (the HyNaCs) via binding to a similar pocket, although there is not yet any experimental evidence. In contrast, RFamide neuropeptides modulate acid‐sensing ion channels (ASICs) from vertebrates via binding to a central cavity enclosed by β‐sheets of the extracellular domain. Dynorphin opioid peptides, for their part, bind to the acidic pocket of ASICs, which might be evolutionarily related to the peptide binding pocket of FaNaCs, but instead of opening the channels they work as antagonists to stabilize its closed state. Moreover, peptides interacting with DEG/ENaCs from animals of different phyla, although having similar sequences, are evolutionarily unrelated to each other. Collectively, it appears that despite a seemingly similar interaction with similar peptides, the interaction of DEG/ENaCs with neuropeptides has diverse structural bases and many origins.

Large-scale deorphanization ofNematostella vectensisneuropeptide GPCRs supports the independent expansion of bilaterian and cnidarian peptidergic systems

“…Overall, we identified receptors for peptides from nearly half of the Nematostella neuropeptide precursors, including the receptors of the ancient PRXamide and pyrQGRFamide peptides. Future studies aiming at finding the remaining receptors could focus on GPCRs with no sequence similarity to known bilaterian neuropeptide GPCRs, including monoamine-related or leucine-rich-repeat receptors, or other types of receptors like DEG/ENaC-related ion channels (Gründer et al, 2022;Mirabeau and Joly, 2013). bachei, Mnemiopsis leydi, Hormiphora californiensis) and the filasterian Tunicaraptor unikontum.…”

“…These include receptors for Hydra vulgaris RFamide peptides and a receptor for a PRXamide maturation-inducing hormone (MIH) in the hydrozoan Clytia hemisphaerica (Artigas et al, 2020; Assmann et al, 2014). Hydra RFamide peptides activate heterotrimeric peptide-gated ion channels belonging to the DEG/ENaC family and distantly related to bilaterian RFamide- and Wamide-gated ion channels (Dandamudi et al, 2022; Elkhatib et al, 2022; Gründer et al, 2022). The Clytia MIH receptor is a class A GPCR, which together with related cnidarian GPCRs shows a many-to-many ortholog relationship to a range of bilaterian neuropeptide GPCR families that also contain receptors for RFamide-like neuropeptides (Artigas et al, 2020).…”

Ion channels and transporters keep ideas flowing

“…Applying this knowledge back to the observations discussed by Gründer et al. (2022), these capabilities enable high‐throughput pharmacology, to gain detailed insights into ASIC modulation kinetics by comprehensive panels of neuropeptides. Summarily, the DEG/ENaC family provides ample opportunities to understand the properties enabling them to behave as successful physiological sensors throughout the animal kingdom.…”

“…This review bridges work arising from genetic and electrophysiological approaches, highlighting the roles of DEG/ENaCs in manifold modes of sensation, in addition to their potential as therapeutic targets (Kaulich, Grundy et al., 2023). Stephan Gründer recounts his symposium presentation, providing a detailed treatment of the structural basis and diversity of neuropeptide gating of invertebrate DEG/ENaC family members (Gründer et al., 2022). Moreover, he presents evidence demonstrating neuropeptide modulation, rather than gating, of distinct regions within vertebrate acid‐sensing ion channels (ASICs).…”

Aromatic amino acids in the finger domain of the FMRFamide-gated Na$$^+$$ channel are involved in the FMRFamide recognition and the activation

“…The degenerin/epithelial sodium channel (DEG/ENaC) family is a diverse family of ion channels which are essential for Na + absorption, mechanotransduction, acid-sensing and peptidergic neurotransmission [24,25,28,35]. The epithelial sodium channels (ENaC) and the acid-sensing ion channels (ASIC) are well studied archetypes in the DEG/ENaC family.…”