Dataset Information

Crotoxin B from the South American Rattlesnake Crotalus vegrandis Blocks Voltage-Gated Calcium Channels Independent of Its Intrinsic Catalytic Activity

ABSTRACT: Neurotoxicity following South American Crotalus rattlesnake bite is primarily caused by crotoxin, the most abundant component in their venom. Despite the central role of volt-age-gated calcium channels (CaV) in neurotransmission, direct targetability by crotoxin has been poorly explored. Crotoxin is a non-covalent heterodimer formed by an acidic subunit (CA) and a basic toxic phospholipase A2 subunit (CB). Here, we chromatograph-ically isolated the CB subunit from Crotalus vegrandis and studied its effect on CaV heter-ologously expressed in HEK293 cells using whole-cell patch-clamp technique. Mass spectrometry analysis identified a protein that matched with 97% sequence coverage the CBc isoform from Crotalus durissus terrificus. Isolated CB exhibited moderate phospholipase activity that was not correlated to its cytotoxic effect on cultured tsA201 cells. Using Ba2+ as charge carrier to prevent the enzymatic activity, we found that CB inhibited currents me-diated by the N-type CaV2.2 and CaV1.2 L-type calcium channels, in a dose-dependent manner, with higher potency for the latter, and negligible changes in the voltage depend-ence of channel activation. Our results reveal a novel phospholipase-independent biolog-ical activity and a novel molecular target of CB providing new insights into the patho-physiology of Crotalus snakebite envenoming with potential clinical therapeutic implica-tions

INSTRUMENT(S):

ORGANISM(S): Crotalus Vegrandis

TISSUE(S): Saliva

SUBMITTER: Beatrix Santiago-Schuebel

LAB HEAD: Dr. Beatrix

PROVIDER: PXD070916 | Pride | 2026-02-02

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	211012_B_FCP_Venom_82J_RA7_1_1791.d.7z	Other
	211012_B_FCP_Venom_82J_RA7_1_1791.mzML	Mzml
	211013_B_FCP_Venom_F75_RB2_1_1798.d.7z	Other
	211013_B_FCP_Venom_F75_RB2_1_1798.mzML	Mzml
	211013_B_FCP_Venom_M75_RB1_1_1800.d.7z	Other

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Publications

Crotoxin B from the South American Rattlesnake Crotalus vegrandis Blocks Voltage-Gated Calcium Channels Independent of Its Intrinsic Catalytic Activity.

Eicheldinger Markus M Miranda-Laferte Erick E Castilla Francisco F Jordan Nadine N Santiago-Schübel Beatrix B Hidalgo Patricia P

Toxins 20260110 1

Neurotoxicity following South American Crotalus rattlesnake bite is primarily caused by crotoxin, the most abundant component in their venom. Despite the central role of voltage-gated calcium channels (CaV) in neurotransmission, direct targetability by crotoxin has been poorly explored. Crotoxin is a non-covalent heterodimer formed by an acidic subunit (CA) and a basic toxic phospholipase A2 subunit (CB). Here, we chromatographically isolated the CB subunit from C ...[more]

PMID: 41591182

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Project description:Chromosomal instability (CIN), defined as an increased occurrence of chromosome segregation errors during cell division, is a prominent form of genomic instability (Bakhoum and Avi Landau, 2017). It is the major cause of aneuploidy, an imbalanced complement of whole chromosomes or chromosome arms, which is the most prevalent genetic alteration in human cancers (Vasudevan et al., 2021; Santaguida and Amon, 2015). Importantly, aneuploidy is commonly associated with ongoing CIN through consecutive cell divisions (Shelzer et al. 2011; Passerini et al., 2016), resulting in intratumor genetic heterogeneity, a central driver of cancer evolution and therapeutic resistance (Sansregret et al., 2018; Ben-David and Amon, 2019). Indeed, aneuploidy has been shown to act both as a tumor suppressor and as a tumor initiator (Weaver et al., 2007; Silk et al., 2013; Vasudevan et al., 2020), most likely depending on the specific chromosomes that are gained or lost (Ben-David et al., 2011; Sack et al., 2018; Adell et al., 2023). Despite the ubiquitous presence of CIN in several aneuploid cancer types and its clinical relevance, its presence in B-cell acute lymphoblastic leukemia (B-ALL) remains largely unexplored owing to the impaired proliferation of leukemic cells in vitro and the lack of reliable experimental models to comprehensively assess chromosome segregation in vivo. B-ALL is the most frequent childhood cancer, with 75% of cases occurring in children under 6 years of age, and it is characterized by the accumulation of highly proliferative immature B-cell precursors in the bone marrow (BM) (Hunger and Mullighan, 2015). The presence of CIN and its contribution to aneuploid cB-ALL progression is largely unknown due to the lack of preclinical models to study actively dividing cells. Accordingly, studies of CIN in cB-ALL are limited to the characterization of chromosomal copy-number heterogeneity (chr-CNH) in primary cB-ALL samples, but there is controversy over its presence due to the different techniques used to assess karyotype variability (Raimondi et al., 1996; Talamo et al., 2010; Alpar et al., 2014; Heerema et al.; 2007; Ramos-Muntada et al., 2022). Here, we explored the presence and the levels of CIN in different clinically-relevant aneuploid subtypes of cB-ALL using single-cell whole-genome sequencing (WGS) of primary samples to reliably assess chr-CNH, and by generating a large cohort of PDX models from primary cB-ALL samples (cB-ALL-PDX). Our results in cB-ALL-PDX models revealed variable levels of CIN in aneuploid cB-ALL subtypes, which significantly correlate with intraclonal karyotype heterogeneity and with disease progression. Additionally, mass-spectrometry analyses of cB-ALL-PDX samples revealed a CIN “signature” enriched in mitosis and chromosome segregation regulatory pathways. We speculate that this signature identifies adaptive mechanisms to ongoing CIN in aneuploid cB-ALL cells, which displayed a transcriptional signature characterized by an impaired mitotic spindle as observed by RNA-sequencing (RNA-Seq) analyses of a large cohort of primary cB-ALL patient samples. Our work might help to improve stratification of patients with cB-ALL with different levels of CIN who could benefit in the future from new therapeutic approaches aiming to target ongoing CIN.

Dataset Information

Crotoxin B from the South American Rattlesnake Crotalus vegrandis Blocks Voltage-Gated Calcium Channels Independent of Its Intrinsic Catalytic Activity

Dataset's files

Publications

Crotoxin B from the South American Rattlesnake <i>Crotalus vegrandis</i> Blocks Voltage-Gated Calcium Channels Independent of Its Intrinsic Catalytic Activity.

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