KB-R7943 inhibits Na+-dependent Mg2+ efflux in rat ventricular myocytes

Tashiro, Michiko; Inoue, Hirokazu; Konishi, Masato

doi:10.1007/s12576-010-0113-z

Cited by 5 publications

(3 citation statements)

References 31 publications

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“…The time course of the [Mg 2+ ] i change could be fitted only partially by the two-phase exponential function. Because this rise of [Mg 2+ ] i could be due to drug-induced toxicity by the high concentration of naltriben, as generally observed in many types of cell damage [15], the results with 100 μM naltriben were not included in the following analyses.…”

Section: Effects Of Naltriben On the Mg 2+ Influxmentioning

confidence: 99%

Modulation of Mg2+ influx and cytoplasmic free Mg2+ concentration in rat ventricular myocytes

2018

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To examine whether TRPM7, a member of the melastatin family of transient receptor potential channels, is a physiological pathway for Mg entry in mammalian cells, we studied the effect of TRPM7 regulators on cytoplasmic free Mg concentration ([Mg]) of rat ventricular myocytes. Acutely isolated single cells were AM-loaded with the fluorescent indicator furaptra, and [Mg] was estimated at 25 °C. After [Mg] was lowered by soaking the cells with a high-K and Mg-Ca-free solution, [Mg] was recovered by extracellular perfusion of Ca-free Tyrode's solution that contained 1 mM Mg. The initial rate of increase in [Mg] was analyzed as the Mg influx rate. The Mg influx rate was increased by the TRPM7 activator, naltriben (2-50 μM), in a concentration-dependent manner with a half maximal effective concentration (EC) of 24 μM. This EC value is similar to that reported for the activation of recombinant TRPM7 overexpressed in HEK293 cells. Naltriben (50 μM) caused little change in basal [Mg] (~ 0.9 mM) in Ca-free Tyrode's solution, but significantly raised [Mg] to 1.31 ± 0.03 mM in 94 min after the removal of extracellular Na. Re-introduction of extracellular Na lowered [Mg] back to the basal level even in the presence of naltriben. Application of 10 μM NS8593, an inhibitor of TRPM7, significantly lowered [Mg] to 0.72 ± 0.03 mM in 50-60 min independent of extracellular Na. The results suggest that Mg entry through TRPM7 significantly contributes to physiological Mg homeostasis in mammalian heart cells.

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Section: Effects Of Naltriben On the Mg 2+ Influxmentioning

confidence: 99%

Modulation of Mg2+ influx and cytoplasmic free Mg2+ concentration in rat ventricular myocytes

2018

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“…The ratio of fluorescence intensities excited at 380 nm and 345 nm was calibrated in terms of [Mg 2+ ] i as described previously. 40 To assess Mg 2+ influx, cells were exposed to a high Mg 2+ , low Na + solution composed of (in mM): 68. Morpholino Oligo-Mediated Knock-Down…”

Section: Measurement Of Magnesium Influx and Effluxmentioning

confidence: 99%

Mutation of the Mg2+ Transporter SLC41A1 Results in a Nephronophthisis-Like Phenotype

Hurd

Otto

Mishima

et al. 2013

Journal of the American Society of Nephrology

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Nephronophthisis (NPHP)-related ciliopathies are recessive, single-gene disorders that collectively make up the most common genetic cause of CKD in the first three decades of life. Mutations in 1 of the 15 known NPHP genes explain less than half of all cases with this phenotype, however, and the recently identified genetic causes are exceedingly rare. As a result, a strategy to identify single-gene causes of NPHP-related ciliopathies in single affected families is needed. Although whole-exome resequencing facilitates the identification of disease genes, the large number of detected genetic variants hampers its use. Here, we overcome this limitation by combining homozygosity mapping with whole-exome resequencing in a sibling pair with an NPHP-related ciliopathy. Whole-exome capture revealed a homozygous splice acceptor site mutation (c.698G.T) in the renal Mg 2+ transporter SLC41A1. This mutation resulted in skipping of exon 6 of SLC41A1, resulting in an in-frame deletion of a transmembrane helix. Transfection of cells with wild-type or mutant SLC41A1 revealed that deletion of exon 6 completely blocks the Mg 2+ transport function of SLC41A1. Furthermore, in normal human kidney tissue, endogenous SLC41A1 specifically localized to renal tubules situated at the corticomedullary boundary, consistent with the region of cystogenesis observed in NPHP and related ciliopathies. Last, morpholino-mediated knockdown of slc41a1 expression in zebrafish resulted in ventral body curvature, hydrocephalus, and cystic kidneys, similar to the effects of knocking down other NPHP genes. Taken together, these data suggest that defects in the maintenance of renal Mg 2+ homeostasis may lead to tubular defects that result in a phenotype similar to NPHP.

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“…We used the parameter values previously estimated in rat ventricular myocytes at 25 C: K D ¼ 5.30 mM, R min ¼ 0.969, and R max ¼ 0.223(1), and at 35 C: K D ¼ 3.387 mM, R min ¼ 0.955, and R max ¼ 0.174(16).…”

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confidence: 99%

Physiological Pathway of Magnesium Influx in Rat Ventricular Myocytes

Tashiro

Inoue

Konishi

2014

Biophysical Journal

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Cytoplasmic free Mg(2+) concentration ([Mg(2+)]i) was measured in rat ventricular myocytes with a fluorescent indicator furaptra (mag-fura-2) introduced by AM-loading. By incubation of the cells in a high-K(+) (Ca(2+)- and Mg(2+)-free) solution, [Mg(2+)]i decreased from ? 0.9 mM to 0.2 to 0.5 mM. The lowered [Mg(2+)]i was recovered by perfusion with Ca(2+)-free Tyrode's solution containing 1 mM Mg(2+). The time course of the [Mg(2+)]i recovery was fitted by a single exponential function, and the first derivative at time 0 was analyzed as being proportional to the initial Mg(2+) influx rate. The Mg(2+) influx rate was inversely related to [Mg(2+)]i, being higher at low [Mg(2+)]i. The Mg(2+) influx rate was augmented by the high extracellular Mg(2+) concentration (5 mM), whereas it was greatly reduced by cell membrane depolarization caused by high K(+). Known inhibitors of TRPM7 channels, 2-aminoethoxydiphenyl borate (2-APB), NS8593, and spermine reduced the Mg(2+) influx rate with half inhibitory concentrations (IC50) of, respectively, 17 ?M, 2.0 ?M, and 22 ?M. We also studied Ni(2+) influx by fluorescence quenching of intracellular furaptra by Ni(2+). The Ni(2+) influx was activated by lowering intra- and extracellular Mg(2+) concentrations, and it was inhibited by 2-APB and NS8593 with IC50 values comparable with those for the Mg(2+) influx. Intracellular alkalization (caused by pulse application of NH4Cl) enhanced, whereas intracellular acidification (induced after the removal of NH4Cl) slowed the Mg(2+) influx. Under the whole-cell patch-clamp configuration, the removal of intracellular and extracellular divalent cations induced large inward and outward currents, MIC (Mg-inhibited cation) currents or IMIC, carried by monovalent cations likely via TRPM7 channels. IMIC measured at -120 mV was diminished to ? 50% by 100 ?M 2-APB or 10 ?M NS8593. These results suggest that TRPM7/MIC channels serve as a major physiological pathway of Mg(2+) influx in rat ventricular myocytes.

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KB-R7943 inhibits Na+-dependent Mg2+ efflux in rat ventricular myocytes

Cited by 5 publications

References 31 publications

Modulation of Mg2+ influx and cytoplasmic free Mg2+ concentration in rat ventricular myocytes

Modulation of Mg2+ influx and cytoplasmic free Mg2+ concentration in rat ventricular myocytes

Mutation of the Mg2+ Transporter SLC41A1 Results in a Nephronophthisis-Like Phenotype

Physiological Pathway of Magnesium Influx in Rat Ventricular Myocytes

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