Evidence of the presence of a calmodulin-sensitive plasma membrane Ca 2+ -ATPase in Trypanosoma equiperdum

Pérez-Gordones, María Carolina; Ramírez-Iglesias, José Rubén; Cervino, Vincenza; Uzcanga, Graciela L.; Benaím, Gustavo; Mendoza, M.

doi:10.1016/j.molbiopara.2017.02.001

Cited by 9 publications

(7 citation statements)

References 61 publications

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“…In T. cruzi the PMCA also has been identified (Benaim et al, 1991), isolated by mean of a CaM-affinity column and partially characterized (Benaim et al, 1995), but appears to diverge from its human counterpart at the CaM-binding domain (Figure 2). Albeit the CaM-binding domain in T. cruzi PMCA (TcCa1) has not been characterized fully, recent studies on Trypanosoma equiperdum (a T. brucei-related hemoflagellate parasite that causes infection in cattle), have demonstrated that the CaM-binding domain of the PMCA of T. equiperdum possesses a non-canonical sequence (Perez-Gordones et al, 2017;Ramírez-Iglesias et al, 2018). This Ca 2+ -ATPase contains a 28 amino acid-region in the C-terminal tail that has been proposed to assume an α-helix conformation within a 1-18 (Trp-1, Phe-18) CaM binding motif (Perez-Gordones et al, 2017).…”

Section: Intracellular Ca 2+ Regulation In Human Cells and Critical Dmentioning

confidence: 99%

“…Albeit the CaM-binding domain in T. cruzi PMCA (TcCa1) has not been characterized fully, recent studies on Trypanosoma equiperdum (a T. brucei-related hemoflagellate parasite that causes infection in cattle), have demonstrated that the CaM-binding domain of the PMCA of T. equiperdum possesses a non-canonical sequence (Perez-Gordones et al, 2017;Ramírez-Iglesias et al, 2018). This Ca 2+ -ATPase contains a 28 amino acid-region in the C-terminal tail that has been proposed to assume an α-helix conformation within a 1-18 (Trp-1, Phe-18) CaM binding motif (Perez-Gordones et al, 2017). Another difference is that unlike CaM in human cells, which interacts with the CaM-binding domain solely with the Cterminal half (78-148 aa) of the PMCA protein (Guerini et al, 1984), T. equiperdum CaM appears to wrap the CaM-binding domain of the parasite PMCA (Perez-Gordones et al, 2017;Ramírez-Iglesias et al, 2018).…”

Section: Intracellular Ca 2+ Regulation In Human Cells and Critical Dmentioning

confidence: 99%

“…This Ca 2+ -ATPase contains a 28 amino acid-region in the C-terminal tail that has been proposed to assume an α-helix conformation within a 1-18 (Trp-1, Phe-18) CaM binding motif (Perez-Gordones et al, 2017). Another difference is that unlike CaM in human cells, which interacts with the CaM-binding domain solely with the Cterminal half (78-148 aa) of the PMCA protein (Guerini et al, 1984), T. equiperdum CaM appears to wrap the CaM-binding domain of the parasite PMCA (Perez-Gordones et al, 2017;Ramírez-Iglesias et al, 2018). The sequence of the CaM-binding domain of T. equiperdum is very similar to that present in the in the T. cruzi PMCA, suggesting that with all likelihood, the characterization performed on the enzyme from T. equiperdum, can be extrapolated to the T. cruzi PMCA.…”

Section: Intracellular Ca 2+ Regulation In Human Cells and Critical Dmentioning

confidence: 99%

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Disruption of Intracellular Calcium Homeostasis as a Therapeutic Target Against Trypanosoma cruzi

Benaím

Paniz‐Mondolfi

Sordillo

et al. 2020

Front. Cell. Infect. Microbiol.

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There is no effective cure for Chagas disease, which is caused by infection with the arthropod-borne parasite, Trypanosoma cruzi. In the search for new drugs to treat Chagas disease, potential therapeutic targets have been identified by exploiting the differences between the mechanisms involved in intracellular Ca 2+ homeostasis, both in humans and in trypanosomatids. In the trypanosomatid, intracellular Ca 2+ regulation requires the concerted action of three intracellular organelles, the endoplasmic reticulum, the single unique mitochondrion, and the acidocalcisomes. The single unique mitochondrion and the acidocalcisomes also play central roles in parasite bioenergetics. At the parasite plasma membrane, a Ca 2+-− ATPase (PMCA) with significant differences from its human counterpart is responsible for Ca 2+ extrusion; a distinctive sphingosine-activated Ca 2+ channel controls Ca 2+ entrance to the parasite interior. Several potential anti-trypansosomatid drugs have been demonstrated to modulate one or more of these mechanisms for Ca 2+ regulation. The antiarrhythmic agent amiodarone and its derivatives have been shown to exert trypanocidal effects through the disruption of parasite Ca 2+ homeostasis. Similarly, the amiodarone-derivative dronedarone disrupts Ca 2+ homeostasis in T. cruzi epimastigotes, collapsing the mitochondrial membrane potential (Ψ m), and inducing a large increase in the intracellular Ca 2+ concentration ([Ca 2+ ] i) from this organelle and from the acidocalcisomes in the parasite cytoplasm. The same general mechanism has been demonstrated for SQ109, a new anti-tuberculosis drug with potent trypanocidal effect. Miltefosine similarly induces a large increase in the [Ca 2+ ] i acting on the sphingosine-activated Ca 2+ channel, the mitochondrion and acidocalcisomes. These examples, in conjunction with other evidence we review herein, strongly support targeting Ca 2+ homeostasis as a strategy against Chagas disease.

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Section: Intracellular Ca 2+ Regulation In Human Cells and Critical Dmentioning

confidence: 99%

Section: Intracellular Ca 2+ Regulation In Human Cells and Critical Dmentioning

confidence: 99%

Section: Intracellular Ca 2+ Regulation In Human Cells and Critical Dmentioning

confidence: 99%

See 1 more Smart Citation

Disruption of Intracellular Calcium Homeostasis as a Therapeutic Target Against Trypanosoma cruzi

Benaím

Paniz‐Mondolfi

Sordillo

et al. 2020

Front. Cell. Infect. Microbiol.

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“…The activity of all PMCA isoforms (and variants) is heavily regulated. Short-term regulation of catalytic activity of most of the “b” or splice site 2 variants is mainly calmodulin-dependent [ 37 , 38 , 39 , 40 ]. The binding of CaM reverses auto-inhibition of the pump due to conformational shifts which displace C-tail from cytosolic loops.…”

Section: Intracellular Ca 2+ Buffers In Normal Cellsmentioning

confidence: 99%

Advances in Intracellular Calcium Signaling Reveal Untapped Targets for Cancer Therapy

2021

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Intracellular Ca2+ distribution is a tightly regulated process. Numerous Ca2+ chelating, storage, and transport mechanisms are required to maintain normal cellular physiology. Ca2+-binding proteins, mainly calmodulin and calbindins, sequester free intracellular Ca2+ ions and apportion or transport them to signaling hubs needing the cations. Ca2+ channels, ATP-driven pumps, and exchangers assist the binding proteins in transferring the ions to and from appropriate cellular compartments. Some, such as the endoplasmic reticulum, mitochondria, and lysosomes, act as Ca2+ repositories. Cellular Ca2+ homeostasis is inefficient without the active contribution of these organelles. Moreover, certain key cellular processes also rely on inter-organellar Ca2+ signaling. This review attempts to encapsulate the structure, function, and regulation of major intracellular Ca2+ buffers, sensors, channels, and signaling molecules before highlighting how cancer cells manipulate them to survive and thrive. The spotlight is then shifted to the slow pace of translating such research findings into anticancer therapeutics. We use the PubMed database to highlight current clinical studies that target intracellular Ca2+ signaling. Drug repurposing and improving the delivery of small molecule therapeutics are further discussed as promising strategies for speeding therapeutic development in this area.

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“…Although some trypanosomatids apparently lack this C -terminal calmodulin binding domain, it has been shown that calmodulin stimulates the plasma membrane ATPase activity in T. brucei [ 40 ], T. cruzi [ 48 ] and L. mexicana [ 49 ]. In this regard, the presence of a CaM-binding domain was recently demonstrated in the C -terminal region of the PMCA of Trypanosoma equiperdum [ 50 , 51 ], a subspecies of T. brucei [ 52 ].…”

Section: Calcium Transport Proteins In the Plasma Membranementioning

confidence: 99%

Membrane Proteins in Trypanosomatids Involved in Ca2+ Homeostasis and Signaling

Ramakrishnan

Docampo

2018

Genes

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Calcium ion (Ca2+) serves as a second messenger for a variety of cell functions in trypanosomes. Several proteins in the plasma membrane, acidocalcisomes, endoplasmic reticulum, and mitochondria are involved in its homeostasis and in cell signaling roles. The plasma membrane has a Ca2+ channel for its uptake and a plasma membrane-type Ca2+-ATPase (PMCA) for its efflux. A similar PMCA is also located in acidocalcisomes, acidic organelles that are the primary Ca2+ store and that possess an inositol 1,4,5-trisphosphate receptor (IP3R) for Ca2+ efflux. Their mitochondria possess a mitochondrial calcium uniporter complex (MCUC) for Ca2+ uptake and a Ca2+/H+ exchanger for Ca2+ release. The endoplasmic reticulum has a sarcoplasmic-endoplasmic reticulum-type Ca2+-ATPase (SERCA) for Ca2+ uptake but no Ca2+ release mechanism has been identified. Additionally, the trypanosomatid genomes contain other membrane proteins that could potentially bind calcium and await further characterization.

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Evidence of the presence of a calmodulin-sensitive plasma membrane Ca 2+ -ATPase in Trypanosoma equiperdum

Cited by 9 publications

References 61 publications

Disruption of Intracellular Calcium Homeostasis as a Therapeutic Target Against Trypanosoma cruzi

Disruption of Intracellular Calcium Homeostasis as a Therapeutic Target Against Trypanosoma cruzi

Advances in Intracellular Calcium Signaling Reveal Untapped Targets for Cancer Therapy

Membrane Proteins in Trypanosomatids Involved in Ca2+ Homeostasis and Signaling

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