Effects of Cobra Cardiotoxins on Intracellular Calcium and the Contracture of Rat Cardiomyocytes Depend on Their Structural Types

Abstract

Cardiotoxins (CaTx) of the three-finger toxin family are one of the main components of cobra venoms. Depending on the structure of the N-terminal or the central polypeptide loop, they are classified into either group I and II or P- and S-types, respectively, and toxins of different groups or types interact with lipid membranes variably. While their main target in the organism is the cardiovascular system, there is no data on the effects of CaTxs from different groups or types on cardiomyocytes. To evaluate these effects, a fluorescence measurement of intracellular Ca2+ concentration and an assessment of the rat cardiomyocytes’ shape were used. The obtained results showed that CaTxs of group I containing two adjacent proline residues in the N-terminal loop were less toxic to cardiomyocytes than group II toxins and that CaTxs of S-type were less active than P-type ones. The highest activity was observed for Naja oxiana cobra cardiotoxin 2, which is of P-type and belongs to group II. For the first time, the effects of CaTxs of different groups and types on the cardiomyocytes were studied, and the data obtained showed that the CaTx toxicity to cardiomyocytes depends on the structures both of the N-terminal and central polypeptide loops.

Specific Amino Acid Residues in the Three Loops of Snake Cytotoxins Determine Their Membrane Activity and Provide a Rationale for a New Classification of These Toxins

“…Thus, CTs with a higher charge will possess higher activity. A recent study of the cytotoxic activity of five CTs (CT1No, CT1Na, CT1Nan, CT2No, and CT2Nan, belonging to groups 5, 5, 1, 8, and 3, respectively) against rat cardiomyocytes is in line with this observation [119]. Four CTs (CT3Nk, CT1No, CT2bNsp, and CT2No from groups 5, 5, 8, and 8) were tested against the infusoria Tetrahymena pyriformis [127].…”

“…The proposed classification of CTs extends their division into either P- or S-types, made by Wu WG et al about 30 years ago [ 112 ]. Since then, due to an absence of alternatives, this division has been used by researchers while comparing cytotoxic and other activities of CTs [ 61 , 114 , 115 , 116 , 117 , 118 , 119 ]. Wu WG et al investigated the membrane activities of nine CTs (CT1Ns, CT1Na, CT2Na, CT3Na, CT4Na, CT1Nm, CT2Nm, CT4Nm, and CT5Nm) ( Table 2 ) and one CLBP A5 ( Table S2 ).…”

Fifty Years of Animal Toxin Research at the Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry RAS

“…However, recent works at IBCh, in collaboration with other institutes of RAS, showed that this activity is also dependent on the structural types of cardiotoxins [ 81 , 82 ]. These differences were observed in the whole heart [ 82 ], isolated muscle and aorta [ 81 ], as well as in cardiomyocytes [ 83 ]. It was shown that the effect of cytotoxins on the cardiovascular system was mainly associated with the disruption of the transport systems responsible for Ca 2+ influx [ 81 ].…”

Molecular Mechanisms of Animal Toxins, Venoms and Antivenoms

“…The immune system is also influenced by these toxins; for example, complement is depleted by the cobra venom factor [4]. The manuscripts submitted to this Special Issue uncover the molecular mechanisms of animal toxin effects on the cardiovascular [5] and immune [6] systems.…”