Dual signaling of Wamide myoinhibitory peptides through a peptide-gated channel and a GPCR in Platynereis

Abstract

Neuropeptides commonly signal by metabotropic G-protein coupled receptors (GPCRs). In some mollusks and cnidarians, RFamide neuropeptides mediate fast ionotropic signaling by peptidegated ion channels that belong to the DEG/ENaC family. Here we describe a neuropeptide system with a dual mode of signaling by both a peptide-gated channel and a GPCR. We identified and characterised a peptide-gated channel in the marine annelid Platynereis dumerilii that is specifically activated by Wamide myoinhibitory peptides derived from the same proneuropeptide. The myoinhibitory peptide-gated ion channel (MGIC) belongs to the DEG/ENaC family and is paralogous to RFamide-gated channels. Platynereis myoinhibitory peptides also activate a previously described GPCR, MAG. We measured the potency of all Wamides on both MGIC and MAG and identified peptides that preferentially activate one or the other receptor. Analysis of a single-cell transcriptome resource indicates that MGIC and MAG signal to distinct target neurons. The identification of a Wamide-gated channel suggests that peptide-gated channels are more diverse and widespread in animals than previously appreciated. The possibility of neuropeptide signaling by both ionotropic and metabotropic receptors to different target cells in the same organism highlights an additional level of complexity in peptidergic signaling networks.

The chemical brain hypothesis for the origin of nervous systems

“…In contrast, peptides have unlimited diversity, with a 5 amino-acid-long form having 20 5 possible variants, not considering modifications (although solubility and stability will somewhat limit the number of variants). Peptides can also easily diversify through the process of gene duplication and divergence or by intra-precursor divergence [77]. The evolution of receptors can follow, through coevolutionary diversification (duplication of both ligand and receptor, followed by the divergence of specificity), a general process in the evolution of peptide-receptor systems [26][27][28].…”

“…B 376: 20190761 receptors? Are there peptide-gated channels in ctenophores, like in Hydra and some bilaterians [77,103,140]? Is the ctenophore nervous system wired into complex peptidergic cellular networks?…”

The chemical brain hypothesis for the origin of nervous systems

“…In contrast, peptides have unlimited diversity with a 5 amino-acid-long form having 20 5 possible variants, not considering modifications. Peptides can also easily diversify through the process of gene duplication and divergence or by intra-precursor divergence [50] . The evolution of receptors can follow, through coevolutionary diversification (duplication of both ligand and receptor, followed by the divergence of specificity), a general process in the evolution of peptide-receptor systems [24,26,27] .…”

Comparative analysis defines a broader FMRFamide-gated sodium channel family and determinants of neuropeptide sensitivity

“…2A,B), much like the previously characterized Platynereis MGIC from the same clade (pink in Fig. 1A, (23)), and we therefore refer to these as Wamide-gated sodium channels (WaNaCs). The AWVGDKSLSWa EC 50 at Capitella WaNaC 212912 was 2 ± 0.2 μM (n = 8) and the KWGGNSRMWa EC 50 at Malacoceros WaNaC C53795 was 340 ± 100 nM (n = 9).…”

“…Activation of annelid FaNaCs by RFamides, FVRIamides, and Wamides contrasts with activation of mollusk FaNaCs by only RFamides (14,23,24) (Fig. 1C).…”