Differences in Ca2+ pumping activity between sub-populations of human red cells

Romero, Pedro; Romero, Eneida A.

doi:10.1016/s0143-4160(97)90028-2

Cited by 39 publications

(29 citation statements)

References 22 publications

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“…34,36 Erythrocyte aging has been associated with alterations in membrane permeability for calcium. [37][38][39] Localized membrane deformation has been associated with increased calcium in the process of apical alignment in the initial steps of malaria invasion. 38 Finally, in sickle cell disease, deoxygenated, circulating erythrocytes exhibit reversible increases in membrane permeability to cations through an as yet unidentified pathway known as P sickle , 40,41 and membrane deformation is necessary for this increase in sickling-induced cation permeability.…”

Section: Discussionmentioning

confidence: 99%

Mutations in the mechanotransduction protein PIEZO1 are associated with hereditary xerocytosis

Zarychanski

Schulz

Houston

et al. 2012

Blood

368

410

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Hereditary xerocytosis (HX, MIM 194380)is an autosomal dominant hemolytic anemia characterized by primary erythrocyte dehydration. Copy number analyses, linkage studies, and exome sequencing were used to identify novel mutations affecting PIEZO1, encoded by the FAM38A gene, in 2 multigenerational HX kindreds. Segregation analyses confirmed transmission of the PIEZO1 mutations and cosegregation with the disease phenotype in all affected persons in both kindreds. All patients were heterozygous for FAM38A mutations, except for 3 patients predicted to be homozygous by clinical and physiologic studies who were also homozygous at the DNA level. The FAM38A mutations were both in residues highly conserved across species and within members of the Piezo family of proteins. PIEZO proteins are the recently identified pore-forming subunits of channels that mediate mechanotransduction in mammalian cells. FAM38A transcripts were identified in human erythroid cell mRNA, and discovery proteomics identified PIEZO1 peptides in human erythrocyte membranes. These findings, the first report of mutation in a mammalian mechanosensory transduction channel-associated with genetic disease, suggest that PIEZO proteins play an important role in maintaining erythrocyte volume homeostasis. IntroductionHereditary xerocytosis (also known as HX or dehydrated stomatocytosis, DHSt; OMIM 194380) is an autosomal dominant hemolytic anemia characterized by primary erythrocyte dehydration. 1 HX erythrocytes exhibit decreased total cation and potassium content that are not accompanied by a proportional net gain of sodium and water. HX patients typically exhibit mild to moderate, compensated hemolytic anemia. Erythrocyte mean corpuscular hemoglobin concentration is increased and erythrocyte osmotic fragility is decreased, both reflecting cellular dehydration.A locus for HX on chromosome 16 (16q23-q24) was first identified in a large, 3-generation Irish family. 2 This locus was refined to D16S511-16qter via study of 10 kindreds with variants of HX, pseudohyperkalemia, or nonimmune hydrops fetalis. 3,4 Recent studies of one of the original HX families from Rochester, NY, 5 and of a large HX family from Manitoba, Canada 6 confirmed the linkage of the disease phenotype to chromosome 16q, and refined the candidate region to 16q24.2-16qter, a 2.4 million-bp interval containing 51 known or predicted genes. 6 To identify the HXassociated genetic locus, we performed high-resolution single nucleotide polymorphism (SNP) typing and whole-exome sequencing on selected persons from both the New York and Canadian HX kindreds.In the refined candidate region, no regions of copy number variation were detected at 16q24.2-16qter. A large region of homozygosity was detected in this region in DNA from a presumed homozygote from the New York kindred. Exome sequencing identified novel mutations affecting PIEZO1 (encoded by the FAM38A gene) in both HX kindreds. Segregation analyses confirmed transmission of the PIEZO1 mutations and cosegregation with the disease phenotype in all...

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Section: Discussionmentioning

confidence: 99%

Mutations in the mechanotransduction protein PIEZO1 are associated with hereditary xerocytosis

Zarychanski

Schulz

Houston

et al. 2012

Blood

368

410

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“…Indeed, considering the kinetics of PMCA activity and the timeframe of ATP release, this mechanism seems feasible. The turnover rate of PMCA is 50-300 per second (56,57), the number of pump units per cell is 400-700 (57), and the increased intracellular Ca 2+ levels in RBCs caused by the mechanical deformation are 12-24 nM (55). Combining these numbers, we estimate a timescale for PMCA to remove the extra Ca 2+ of 30-100 ms, which is comparable with the duration of ATP release (∼100 ms).…”

Section: On Intracellular Camentioning

confidence: 94%

Piezo1 regulates mechanotransductive release of ATP from human RBCs

Çinar

Zhou

DeCourcey

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

163

157

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Piezo proteins (Piezo1 and Piezo2) are recently identified mechanically activated cation channels in eukaryotic cells and associated with physiological responses to touch, pressure, and stretch. In particular, human RBCs express Piezo1 on their membranes, and mutations of Piezo1 have been linked to hereditary xerocytosis. To date, however, physiological functions of Piezo1 on normal RBCs remain poorly understood. Here, we show that Piezo1 regulates mechanotransductive release of ATP from human RBCs by controlling the shear-induced calcium (Ca 2+ ) influx. We find that, in human RBCs treated with Piezo1 inhibitors or having mutant Piezo1 channels, the amounts of shear-induced ATP release and Ca 2+ influx decrease significantly. Remarkably, a critical extracellular Ca 2+ concentration is required to trigger significant ATP release, but membrane-associated ATP pools in RBCs also contribute to the release of ATP. Our results show how Piezo1 channels are likely to function in normal RBCs and suggest a previously unidentified mechanotransductive pathway in ATP release. Thus, we anticipate that the study will impact broadly on the research of red cells, cellular mechanosensing, and clinical studies related to red cell disorders and vascular disease. Previous studies have shown that the addition of chemicals that stiffen RBC membranes decreases the amount of ATP released (9, 16), indicating that deformation of the cell membrane is a necessary trigger. In addition, biological mediators, such as cystic fibrosis transmembrane conductance regulator (CFTR) and pannexin-1 hemichannels, are involved in the release pathways of mechanotransductive ATP release from RBCs (9,14,17,18). Inhibition of CFTR leads to an impaired ATP release from deformed RBCs (14). Recent studies, including our previous findings, suggest that interactions between membrane-associated actin and CFTR play important roles in the mechanotransductive ATP release from RBCs (9, 17). Pannexin-1, however, is a channel-forming protein and has been suggested as a mechanosensing ATP release channel (18). Under osmotic stress, for example, ATP released from RBCs was attenuated by carbenoxolone, a highly effective pannexin channel blocker, suggesting that pannexin-1 might be one of the conductance channels responsible for the mechanotransductive release of ATP (18). Although progress has been made in understanding mechanotransductive ATP release from RBCs, many questions remain about the signal transduction pathways. For example, how does mechanical force transduce signals to ATP release channels? Are there any stretch-activated ion channels on RBCs that may sense mechanical forces and activate ATP release? If so, are there any secondary messengers that could be generated by mechanical stimuli and regulate ATP release?Piezo proteins (Piezo1 and Pizeo2) are recently identified mechanically activated cation channels in mammals (19,20) and can be fully activated without involvement of additional proteins (20, 21). Piezo-induced cationic currents were first observe...

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“…Circulatory shear stress has been suggested to cause reversible increases in erythrocyte calcium permeability (36,40). Erythrocyte aging has been associated with alterations in membrane permeability for calcium (41)(42)(43). Localized membrane deformation has been associated with increased calcium in the process of apical alignment in the initial steps of malaria invasion (42).…”

Section: Piezo1 In Erythrocytesmentioning

confidence: 99%