Identification and electrophysiological properties of a sphingosine‐dependent plasma membrane Ca2+ channel in Trypanosoma cruzi
2019
Rodriguez‐Duran, Jessica | Pinto‐Martinez, Andrea | Castillo, Cecilia | Benaim, Gustavo
Trypanosoma cruzi is the causative agent of Chagas disease. The only two drugs accepted for the treatment of this infection are benznidazole and nifurtimox, which are of limited use in the predominant chronic phase. On the search for new drugs, the intracellular Ca²⁺ regulation has been postulated as a possible target, due to differences found between host cells and the parasite. The mechanisms involved in the intracellular Ca²⁺ regulation of T. cruzi have been partially elucidated. However, nothing is known about a putative channel responsible for the Ca²⁺ entry into this parasite. In contrast, in Leishmania spp., a closely related hemoflagelate, a sphingosine‐activated plasma membrane Ca²⁺ channel has been recently described. The latter resembles the L‐type voltage‐gated Ca²⁺ channel present in humans, but with distinct characteristics. This channel is one of the main targets concerning the mechanism of action of miltefosine, the unique oral drug approved against leishmaniasis. In the present work, we describe for the first time, the electrophysiological characterization of a sphingosine‐activated Ca²⁺ channel of T. cruzi by reconstituting plasma membrane vesicles into giant liposomes and patch clamp. This channel shares some characteristic as activation by Bay K8644 and inhibition by channel blockers such as nifedipine. However, the T. cruzi channel differs from the L‐type VGCC in its activation by sphingosine and/or miltefosine. Albeit the conductance for each, Ba²⁺, Ca²⁺ and Sr²⁺ was similar, the parasite channel appears not to be voltage dependent. A gene that presents homology in critical amino acids with its human ortholog Ca²⁺ channel was identified.
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