title: Inositol 1,4,5-trisphosphate receptor regulates replication, differentiation, infectivity and virulence of the parasitic protist Trypanosoma cruzi.
abstract: In animals, inositol 1,4,5-trisphosphate receptors (IP3 Rs) are ion channels that play a pivotal role in many biological processes by mediating Ca(2+) release from the endoplasmic reticulum. Here, we report the identification and characterization of a novel IP3 R in the parasitic protist, Trypanosoma cruzi, the pathogen responsible for Chagas disease. DT40 cells lacking endogenous IP3 R genes expressing T. cruzi IP3 R (TcIP3 R) exhibited IP3 -mediated Ca(2+) release from the ER, and demonstrated receptor binding to IP3 . TcIP3 R was expressed throughout the parasite life cycle but the expression level was much lower in bloodstream trypomastigotes than in intracellular amastigotes or epimastigotes. Disruption of two of the three TcIP3 R gene loci led to the death of the parasite, suggesting that IP3 R is essential for T. cruzi. Parasites expressing reduced or increased levels of TcIP3 R displayed defects in growth, transformation and infectivity, indicating that TcIP3 R is an important regulator of the parasite's life cycle. Furthermore, mice infected with T. cruzi expressing reduced levels of TcIP3 R exhibited a reduction of disease symptoms, indicating that TcIP3 R is an important virulence factor. Combined with the fact that the primary structure of TcIP3 R has low similarity to that of mammalian IP3 Rs, TcIP3 R is a promising drug target for Chagas disease.
authors: Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. muneaki@juntendo.ac.jp
authors: Muneaki
authors: M
authors: Hashimoto
authors: Masahiro
authors: M
authors: Enomoto
authors: Jorge
authors: J
authors: Morales
authors: Nagomi
authors: N
authors: Kurebayashi
authors: Takashi
authors: T
authors: Sakurai
authors: Tetsuo
authors: T
authors: Hashimoto
authors: Takeshi
authors: T
authors: Nara
authors: Katsuhiko
authors: K
authors: Mikoshiba
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000469:parasitology / Q000473:pathology; D016054:DNA, Protozoan / Q000737:chemistry / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D020043:Genes, Essential; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D014349:Trypanosoma cruzi / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity / Q000502:physiology*; D014774:Virulence; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D016054:DNA, Protozoan; D053496:Inositol 1,4,5-Trisphosphate Receptors; D037521:Virulence Factors; D015544:Inositol 1,4,5-Trisphosphate