A previously unrecognized superfamily of macro-conotoxins includes an inhibitor of the sensory neuron calcium channel Cav2.3

Celeste M. Hackney, Paula Flórez Salcedo, Emilie Mueller, Thomas Lund Koch, Lau D. Kjelgaard, Maren Watkins, Linda Zachariassen, Pernille Sønderby Tuelund, Jeffrey R. McArthur, David J. Adams, Anders S. Kristensen, Baldomero Olivera, Rocio K. Finol-Urdaneta, Helena Safavi-Hemami, Jens Preben Morth, Lars Ellgaard*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

102 Downloads (Pure)

Abstract

Animal venom peptides represent valuable compounds for biomedical exploration. The venoms of marine cone snails constitute a particularly rich source of peptide toxins, known as conotoxins. Here, we identify the sequence of an unusually large conotoxin, Mu8.1, which defines a new class of conotoxins evolutionarily related to the well-known con-ikot-ikots and 2 additional conotoxin classes not previously described. The crystal structure of recombinant Mu8.1 displays a saposin-like fold and shows structural similarity with con-ikot-ikot. Functional studies demonstrate that Mu8.1 curtails calcium influx in defined classes of murine somatosensory dorsal root ganglion (DRG) neurons. When tested on a variety of recombinantly expressed voltage-gated ion channels, Mu8.1 displayed the highest potency against the R-type (Cav2.3) calcium channel. Ca2+ signals from Mu8.1-sensitive DRG neurons were also inhibited by SNX-482, a known spider peptide modulator of Cav2.3 and voltage-gated K+ (Kv4) channels. Our findings highlight the potential of Mu8.1 as a molecular tool to identify and study neuronal subclasses expressing Cav2.3. Importantly, this multidisciplinary study showcases the potential of uncovering novel structures and bioactivities within the largely unexplored group of macro-conotoxins.
Original languageEnglish
Article numbere3002217
JournalPLOS Biology
Volume21
Issue number8
Number of pages32
ISSN1544-9173
DOIs
Publication statusPublished - 2023

Fingerprint

Dive into the research topics of 'A previously unrecognized superfamily of macro-conotoxins includes an inhibitor of the sensory neuron calcium channel Cav2.3'. Together they form a unique fingerprint.

Cite this