Benaim Gustavo, Calderón Artavia Christian Gabriel, Castillo Cecilia, Pérez-Gordones María Carolina, Serrano María Luisa
Unidad de Señalización Celular y Bioquímica de Parásitos, Instituto de Estudios Avanzados (IDEA), Caracas, Venezuela.
Instituto de Biología Experimental. Facultad de Ciencias, Universidad Central de Venezuela, Caracas, Venezuela.
Biophys Rev. 2025 Mar 22;17(2):709-722. doi: 10.1007/s12551-025-01300-2. eCollection 2025 Apr.
Ca⁺ 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 Ca concentration ([Ca⁺]) 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 [Ca], whereas a plasma membrane Ca channel is responsible for Ca entry and a Ca-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 Ca⁺ 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 Ca⁺ channel exhibits functional and structural homology with the mammalian counterpart.
钙离子（Ca⁺）在包括锥虫在内的所有真核细胞的信号通路中起着至关重要的作用。锥虫是一大类寄生虫，包括几种人类传染病的病原体，如恰加斯病和利什曼病。因此，细胞内游离钙浓度（[Ca⁺]）受到严格调控。在这些寄生虫中，包括单个线粒体、内质网和酸性钙小体在内的各种细胞内细胞器将胞质浓度维持在约100 nM，这些细胞器作为分隔区，容量有限。因此，质膜机制负责确保[Ca]的长期调节，而质膜钙通道负责钙离子的进入，钙ATP酶则调节钙离子的排出。然而，在诱导其开放的配体被确定之前，该通道的鉴定一直是一个挑战：鞘脂类神经鞘氨醇。米替福新是目前唯一被批准用于治疗利什曼病的口服药物，已被证明可模拟神经鞘氨醇。这篇综述概述了锥虫钙离子通道的历史，从其最初发现开始，到被整合到巨型脂质体中结束。这使得该通道能够通过使用“膜片钳”技术的电生理研究来进行表征。与人类同源物相比，这些研究揭示了相似之处和显著差异，这些差异可用于治疗目的。鉴于先前的研究表明各种锥虫中可能存在L型电压门控钙通道，我们对推定的基因组序列进行了比较分析，结果表明，尽管一级序列同一性水平较低，但这种钙离子通道与哺乳动物的对应物在功能和结构上具有同源性。
