Abnormal regulation of Mg2+ transport via Na/Mg exchanger in sickle erythrocytes

Rivera, Alicia; Ferreira, Ana; Bertoni, Danielle; Romero, José R.; Brugnara, Carlo

doi:10.1182/blood-2003-11-3755

Cited by 21 publications

(19 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A small but statistically significant increase in the MCV of KO erythrocyes was found (Table 2). Mechanistically, partial inhibition of the Gardos channel and KCC1 (Figure 5A), and an increase in the intracellular magnesium concentration (Table 2), could potentially contribute to modest MCV increase in KO erythrocytes, since these systems are known to play a functional role in erythrocyte volume regulation [16,39,40]. Alternatively, calpain-1 loss may trigger down-regulation of as yet unknown membrane-associated protein phosphatases, thus causing inhibition of the KCC1 [41,42].…”

Section: Discussionmentioning

confidence: 99%

Calpain-1 knockout reveals broad effects on erythrocyte deformability and physiology

Wieschhaus

Khan

Zaidi

et al. 2012

Biochemical Journal

Self Cite

View full text Add to dashboard Cite

Pharmacological inhibitors of cysteine proteases have provided useful insights into the regulation of calpain activity in erythrocytes. However, the precise biological function of calpain activity in erythrocytes remains poorly understood. Erythrocytes express calpain-1, an isoform regulated by calpastatin, the endogenous inhibitor of calpains. In the present study, we investigated the function of calpain-1 in mature erythrocytes using our calpain-1-null [KO (knockout)] mouse model. The calpain-1 gene deletion results in improved erythrocyte deformability without any measurable effect on erythrocyte lifespan in vivo. The calcium-induced sphero-echinocyte shape transition is compromised in the KO erythrocytes. Erythrocyte membrane proteins ankyrin, band 3, protein 4.1R, adducin and dematin are degraded in the calcium-loaded normal erythrocytes but not in the KO erythrocytes. In contrast, the integrity of spectrin and its state of phosphorylation are not affected in the calcium-loaded erythrocytes of either genotype. To assess the functional consequences of attenuated cytoskeletal remodelling in the KO erythrocytes, the activity of major membrane transporters was measured. The activity of the K+–Cl− co-transporter and the Gardos channel was significantly reduced in the KO erythrocytes. Similarly, the basal activity of the calcium pump was reduced in the absence of calmodulin in the KO erythrocyte membrane. Interestingly, the calmodulin-stimulated calcium pump activity was significantly elevated in the KO erythrocytes, implying a wider range of pump regulation by calcium and calmodulin. Taken together, and with the atomic force microscopy of the skeletal network, the results of the present study provide the first evidence for the physiological function of calpain-1 in erythrocytes with therapeutic implications for calcium imbalance pathologies such as sickle cell disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Calpain-1 knockout reveals broad effects on erythrocyte deformability and physiology

Wieschhaus

Khan

Zaidi

et al. 2012

Biochemical Journal

Self Cite

View full text Add to dashboard Cite

show abstract

“…NME is a critical modulator of intracellular Mg 2+ and therefore important regulator of cation transport and volume regulatory mechanisms in erythrocytes [19]. We studied the activity of NME in these KO mice.…”

Section: Resultsmentioning

confidence: 99%

“…Its activity is altered in many pathological diseases such as diabetes [26], sickle cell disease [19], and hypertension [27]. Mg 2+ is a well-described regulator of many enzymes and has been shown to play important roles in many cellular functions including cellular volume regulation.…”

Section: Discussionmentioning

confidence: 99%

Ablation of the Kell/Xk complex alters erythrocyte divalent cation homeostasis

Rivera

Kam

et al. 2013

Blood Cells, Molecules, and Diseases

Self Cite

View full text Add to dashboard Cite

XK is a putative transporter of unknown function that is ubiquitously expressed and linked through disulfide bonds to Kell protein, an endothelin-3 (ET-3)-converting enzyme. We generated three knockout (KO) mice that lacked either Xk, Kell or both proteins and characterized erythrocyte cation levels, transport and hematological parameters. Absence of Xk or Kell was accompanied by changes in erythrocyte K+, Mg2+, Na+ and Ca2+ transport that were associated with changes in mean cellular volume and corpuscular hemoglobin concentration mean. Baseline Ca2+-ATPase activity was undetected in erythrocytes from all three mouse types but was restored upon pre-incubation with ET-3. Consistent with these alterations in Ca2+ handling, we observed increased Gardos channel activity in Kel and Xk KO mice. In addition Kel deletion was associated with increased Mg2+ permeability while Xk deletion blocked Na/Mg exchanger activity. Our results provide evidence that cellular divalent cation regulation is functionally coupled to the Kell/XK system in erythrocytes and loss of this complex may contribute to acanthocytosis formation in McLeod syndrome.

show abstract

“…must be recalled. Inhibition of the Gardos channels by senicapoc [13] and modulation of the K-Cl transport system by Mg 2þ achieved improved biologic parameter values [11,14,15], with increased hemoglobin levels, and decreased hemolysis factors and levels of dense RBCs (DRBCs), which are extremely dehydrated, rigid and deformed RBCs [16,17]. Intracellular RBC dehydration, not to be confused with extracellular dehydration, is one of the major factors contributing to HbS polymerization because of the increased intraerythrocyte HbS concentration [11,12].…”

Section: Key Pointsmentioning

confidence: 99%