Elucidation of Medusozoan (Jellyfish) Venom Constituent Activities Using Constellation Pharmacology

• Published in: Toxins Vol. 16; no. 10; p. 447
• Main Authors: Yanagihara, Angel A, Giglio, Matías L, Hurwitz, Kikiana, Kadler, Raechel, Espino, Samuel S, Raghuraman, Shrinivasan, Olivera, Baldomero M
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 17-10-2024; MDPI
• Subjects: Animals; Biological activity; Biomedical materials; box jellyfish; Calcium; Calcium - metabolism; Calcium compounds; Calcium imaging; Calcium Signaling - drug effects; Calcium signalling; Cell death; Cells, Cultured; Cnidaria; Cnidarian Venoms - chemistry; Cnidarian Venoms - pharmacology; constellation pharmacology; cubozoa; Dorsal root ganglia; Fractions; Fura-2; Fura-2 calcium imaging; Ganglia; Ganglia, Spinal - drug effects; Genotype & phenotype; Glial cells; Identification; Ion channels; Ligands; Mice; Mice, Inbred C57BL; Molecular weight; Neuromodulation; Neuronal-glial interactions; Neurons; Neurons - drug effects; Pathophysiology; Peptides; Pharmacology; Phenotypes; Physalia; Physalia physalis; Physiological effects; Physiology; Pore formation; Potassium chloride; Sea Anemones; Venom; glial cells; box jellyfish; ion-channel modulator; venom; cubozoa; Fura-2 calcium imaging; Physalia; dorsal root ganglia; constellation pharmacology; neurons
• ISSN: 2072-6651; 2072-6651
• DOI: 10.3390/toxins16100447

Within the phylum Cnidaria, sea anemones (class Anthozoa) express a rich diversity of ion-channel peptide modulators with biomedical applications, but corollary discoveries from jellyfish (subphylum Medusozoa) are lacking. To bridge this gap, bioactivities of previously unexplored proteinaceous and small molecular weight (~15 kDa to 5 kDa) venom components were assessed in a mouse dorsal root ganglia (DRG) high-content calcium-imaging assay, known as constellation pharmacology. While the addition of crude venom led to nonspecific cell death and Fura-2 signal leakage due to pore-forming activity, purified small molecular weight fractions of venom demonstrated three main, concentration-dependent and reversible effects on defined heterogeneous cell types found in the primary cultures of mouse DRG. These three phenotypic responses are herein referred to as phenotype A, B and C: excitatory amplification (A) or inhibition (B) of KCl-induced calcium signals, and test compound-induced disturbances to baseline calcium levels (C). Most notably, certain
venom fractions showed phenotype A effects in all DRG neurons;
and
fractions predominantly showed phenotype B effects in small- and medium-diameter neurons. Finally, specific
and
venom components induced direct excitatory responses (phenotype C) in glial cells. These findings demonstrate a diversity of neuroactive compounds in jellyfish venom potentially targeting a constellation of ion channels and ligand-gated receptors with broad physiological implications.