The discovery of the Sph-gated plasma membrane Ca2+ channel in trypanosomatids. A difficult path for a surprising kind of L-Type VGCC.

Ca²⁺ plays a crucial role in signaling pathways in all eukaryotic cells, including trypanosomatids. These represent a large family of parasites including the causative agents of several human infectious diseases, such as Chagas' disease and leishmaniasis. Accordingly, the intracellular free Ca²⁺ concentration ([Ca²⁺]_i) is subject to rigorous regulation. In these parasites, the cytosolic concentration is maintained at approximately 100 nM by various intracellular organelles, including the single mitochondrion, the endoplasmic reticulum, and acidocalcisomes, which as compartments, are limited to capacity confines. It is therefore the responsibility of plasma membrane mechanisms to ensure the long-term regulation of [Ca²⁺]_i, whereas a plasma membrane Ca²⁺ channel is responsible for Ca²⁺ entry and a Ca²⁺-ATPase regulates extrusion. However, the identification of this channel has remained a challenge until the ligand that induces its opening was identified: the sphingolipid sphingosine. Miltefosine, the only oral medication currently approved for the treatment of leishmaniasis, has been shown to mimic sphingosine. This review outlines the history of the trypanosomatid Ca²⁺ channel, beginning with its initial discovery and concluding with its incorporation into giant liposomes. This enabled the channel to be characterized by electrophysiological studies using "patch clamp" techniques. These studies revealed similarities and significant differences when compared with the human orthologue, which could be exploited for therapeutic purposes. Given that previous research has indicated the potential existence of an L-type VGCC in various trypanosomatids, we conducted a comparative analysis of putative genomic sequences, which demonstrated that, despite the low level of primary identity, this Ca²⁺ channel exhibits functional and structural homology with the mammalian counterpart.