Mouse Piezo1 ( Piezo-type mechanosensitive ion channel component 1) ELISA Kit

Piezo1 represents a prototype of the mammalian mechanosensitive cation channel, but its molecular mechanism remains elusive. In a recent study, we showed that C-terminal region, which contains the last two TMs, of 2189-2547 of Piezo1 forms the bona fide pore module, and systematically identified the pore-lining helix and key pore-property-determining residues (Zhao et al., 2016). Furthermore, we have engineered the Piezo1(1-2190)-ASIC1 chimera (fusing the N-terminal region of 1-2190 to the mechano-insensitive ASIC1) that mediated mechanical-and acid-evoked currents in HEK293T cells, indicating the sufficiency of the N-terminal region in mechanotransduction. Now in a Matters Arising, the authors specifically questioned the implication of the chimera data among the many findings shown in our paper. They replicated the chimera-mediated mechanosensitive currents in HEK293T cells that have nearly no detectable expression of endogenous Piezo1, but paradoxically found the chimera to be less effective in Piezo1 knockout HEK293T cells, indicating the involvement of endogenous Piezo1. In this Matters Arising Response, we discuss the chimera results and consider potential interpretations in light of the Matters Arising from Dubin et al. (2017), published concurrently in this issue of Neuron. Please see also the response from Hong et al. (2017), published in this issue.

Malaria caused by the apicomplexan parasite Plasmodium falciparum has served as a strong evolutionary force throughout human history, selecting for red blood cell polymorphisms that confer innate protection against severe disease. Recently, gain-of-function mutations in the mechanosensitive ion channel PIEZO1 were shown to ameliorate Plasmodium parasite growth, blood-brain barrier dysfunction, and mortality in a mouse model of malaria. In humans, the gain-of-function allele PIEZO1 E756del is highly prevalent and enriched in Africans, raising the possibility that it is under positive selection due to malaria. Here we used a case-control study design to test for an association between PIEZO1 E756del and malaria severity among children in Gabon. We found that the E756del variant is strongly associated with protection against severe malaria in heterozygotes. In subjects with sickle cell trait, heterozygosity for PIEZO1 E756del did not confer additive protection and homozygosity was associated with an elevated risk of severe disease, suggesting an epistatic relationship between hemoglobin S and PIEZO1 E756del. Using donor blood samples, we show that red cells heterozygous for PIEZO1 E756del are not dehydrated and can support the intracellular growth of P. falciparum similar to wild-type cells. However, surface expression of the P. falciparum virulence protein PfEMP-1 was significantly reduced in infected cells heterozygous for PIEZO1 756del, a phenomenon that has been observed with other protective polymorphisms, such as hemoglobin C. Our findings demonstrate that PIEZO1 is an important innate determinant of malaria susceptibility in humans and suggest that the mechanism of protection may be related to impaired export of P. falciparum virulence proteins.