Table 1.
Ion channels in pathogenic trypanosomatids.
Table 2.
Ion channels in apicomplexans and other pathogenic protozoans.
Fig 1.
Channels and transporters involved in maintenance of the membrane potential in nonexcitable mammalian cells (A) and trypanosomes (B). In nonexcitable mammalian cells, the resting membrane potential (Vm) is maintained at values close to −30 mV by the coordinated activity of ion channels and transporters. This membrane potential is driven by a high permeability to K+ caused by the abundant expression of leak K+ channels. Na+ influx via channels, exchangers, and cotransporters is counterbalanced by the activity of the Na+/K+ ATPase, main membrane pump found in vertebrates. Cl−, the most abundant intracellular anion, is regulated by electroneutral transporters such as the Cl−-Na+-K+ cotransporter and by ClC channels. While Ca2+ influx via VGCCs does not cause a significant change in the membrane potential directly, the cascade of signaling events associated with Ca2+ entry affects expression and trafficking of the channels and transporters mentioned above. In trypanosomatids, and other protozoan parasites studied to date, membrane potential is driven by a proton motive force generated by the activity of H+ ATPases, establishing a value of about −100 mV for T. cruzi epimastigotes. Depending on the life stages analyzed, K+ plays a secondary role on Vm maintenance and the hyperpolarization supports the influx of K+ by channels and/or via exchangers. No Na+ channels have been identified but permeation occurs through NSCCs and exchangers, while efflux is mediated by ENa ATPases. Figure created with BioRender.com. NSCC, nonselective cation channel; VGCC, voltage-gated Ca2+ channel.
Fig 2.
Mechanisms of osmoregulation in Trypanosoma cruzi.
In T. cruzi, cell volume regulation is controlled by the CVC and the ACCS (reviewed in [247]). Both organelles are rich in ions accumulated by the activity of pumps located on their membranes. Upon hypoosmotic stress, ACCS fuse with the CVC transferring Pi, Ca2+, and AA. This concentration of osmolytes drives water into the vacuole via AQP1, causing swelling of the bladder that can be sensed by a mechanosensitive channel (MscS). Contact between the CVC membrane and the flagellar pocket induces the formation of a transient pore that mediates the discharge of water and osmolytes to the EC space. Some ions, like Pi, are not released but instead recovered by transporters (Pho1). These events are accompanied by increase in cAMP and a rise in cytosolic Ca2+ required for volume recovery. Trypanosoma brucei does not possess a contractile vacuole and regulates cellular volume via aquaporins, with AQP2 residing in the flagellar membrane and AQP3 at the plasma membrane. Figure created with BioRender.com. AA, amino acid; ACCS, acidocalcisome; CVC, contractile vacuole complex; EC, extracellular; Pi, phosphate.
Fig 3.
Ion channels postulated as targets for antiparasitic drug development.
Three sets of ion channels have been suggested as potential drug targets against protozoan parasites: (1) proteins located in the host cell membrane and the PV (A); (2) those expressed at the plasma membrane of the parasites; and (3) channels found in intracellular organelles. (A) Plasmodium parasites residing intracellularly export proteins like PSAC to the host cell. Thus, parasites control the import of nutrients while also exploiting proteins from the host cell to create favorable conditions for their growth. AQP9 and PIEZO1 activity increases in infected RBC, and VRAC activity is stimulated in liver cells by Plasmodium infection. Blockage of these proteins severely impacts parasite growth, suggesting their potential as drug targets. Similarly, interference with the activity of pore-forming proteins in the PVM such as EXP2 in Plasmodium and GRA17/GRA23 in Toxoplasma gondii blocks nutrient import and parasite growth. (B) In apicomplexans, blockers of the Na+ pump ATP4 impact parasite growth and PfATP4 has been shown susceptibility to a large number of compounds. Plasma membrane calcium pump (PMCA) and TPPL2 Ca2+ channels are essential for T. gondii tachyzoite growth, and so it is the SERCA pump in the ER, showing that Ca2+ homeostasis is a promising target for drug development. Additional proteins worth to explore in T. gondii are the apicoplast two-pore channel TPC and mitochondrial porin VDAC. (C) In trypanosomatids, Ca2+ controlling proteins including calcium channels (VGCC, IP3 receptors, VDAC, and MCU) and the PMCA have been proposed as druggable targets. Expression of H+-ATPases and K+ channels with very low homology with mammalian proteins could offer an opportunity for the development of selective inhibitors. Modulation of AQP activity is associated with resistance to anti-leishmania therapy and could be exploited as a permeation pathway for chemotherapy. Figure created with BioRender.com. ER, endoplasmic reticulum; MCU, mitochondrial calcium uniporter; PSAC, plasmodial surface anion channel; PV, parasitophorous vacuole; PVM, parasitophorous vacuole membrane; RBC, red blood cell; VDAC, voltage-dependent anion channel; VGCC, voltage-gated Ca2+ channel; VRAC, volume-regulated anion channel.