New patches in the molecular understanding of renal magnesium handling

Contains fulltext : 84459.pdf (publisher's version ) (Open Access)Radboud Universiteit Nijmegen, 25 februari 2011Promotores : Hoenderop, J.G.J., Bindels, R.J.M.198 p

Mg2+ homeostasis: the balancing act of TRPM6.

PURPOSE OF REVIEW: The tight control of blood magnesium (Mg) levels is of central importance for numerous physiological processes. A persistent low Mg status (hypomagnesemia) is associated with severe health risks and is involved in the pathogenesis of type 2 diabetes mellitus, osteoporosis, asthma, and heart and vascular diseases. The current view has expanded significantly as a result of the identification of novel genes and regulatory pathways involved in hypomagnesemic disorders. This review aims to give an up-to-date overview of transient receptor potential melastatin 6 (TRPM6) regulation and its role in the maintenance of Mg homeostasis. RECENT FINDINGS: The epithelial Mg channel TRPM6 is considered to be the Mg entry pathway in the distal convoluted tubule of the kidney, where it functions as gatekeeper for controlling the body's Mg balance. Various factors and hormones contribute not only to the function, but also to the dysregulation of TRPM6, which has a substantial impact on renal Mg handling. Recent genetic and molecular studies have further elucidated the signaling processes of epithelial Mg transport, including their effect on the expression and function of TRPM6. SUMMARY: Knowledge of TRPM6 functioning is of vital importance to decipher its role in Mg handling and will, in particular, provide a molecular basis for achieving a better understanding of Mg mal(re)absorption and hence systemic Mg balance

Epithelial Mg2+ channel TRPM6: insight into the molecular regulation.

Contains fulltext : 80777.pdf (publisher's version ) (Closed access)Our understanding of the molecular mechanisms of renal magnesium (Mg2+) handling has greatly enhanced over recent years. This review highlights the regulatory factors controlling Mg2+ homeostasis through its effects on the epithelial Mg2+ channel TRPM6 (Transient Receptor Potential Melastatin subtype 6), the gatekeeper of the body's Mg2+ balance. Drug treatment, acid-base status, and several hormones have been shown to regulate TRPM6 expression, while its channel activity is modified by intracellular Mg2+, pH, and ATP. Recently, epidermal growth factor (EGF) and estrogen have been implicated as magnesiotropic hormones. The stimulation of the EGF receptor (EGFR) leads to an intracellular cascade involving Rac1 that promotes trafficking of TRPM6 to the plasma membrane. Furthermore, long-term EGF treatment upregulates the expression of TRPM6. Estrogen has also been shown to stimulate TRPM6 activity upon short-term treatment, next to its long-term regulatory effect on TRPM6 transcription. TRPM6, and its closest homologue TRPM7, are composed of a Mg2+ -permeable channel fused to an alpha-kinase domain. In the intracellular compartment, the receptor for activated C-kinase (RACK1), the repressor for estrogen receptor activity (REA), and ATP were identified as negative modulators of TRPM6 activity through its alpha-kinase domain. Therefore, the a-kinase domain acts as an indirect player involved in Mg2+ homeostasis by its feedback function in the TRPM6-mediated Mg2+ influx

Interplay between purinergic signalling and extracellular vesicles in health and disease.

Purinergic signalling is a receptor-mediated process characterized by the binding of extracellular nucleotides and nucleosides to purinergic receptors, which results in the activation intracellular signalling pathways, and, ultimately, leads to changes in cell physiology. Purinergic signalling has been related to the regulation of important physiological processes (e.g., renal electrolyte reabsorption; platelet aggregation; immune response). In addition, it has been associated with pathophysiological situations such as cancer and inflammation. Extracellular vesicles (EVs) are nanoparticles released by all cells of the organism, which play a key role in cell-cell communication. In this regard, EVs can mediate effects on target cells located at distant locations. Within their cargo, EVs contain molecules with the potential to affect purinergic signalling at the target cells and tissues. Here, we review the studies addressing the regulation of purinergic signalling by EVs based on the cell type or tissue where the regulation takes place. In this regard, EVs are found to play a major role in modulating the extracellular ATP levels and, specially, adenosine. This has a clear impact on, for instance, the inflammatory and immune response against cancer cells. Furthermore, we discuss the data available on the regulation of EV secretion and its cargo by purinergic signalling. Here, a major role of the purinergic receptor P2X7 and again, an impact on processes such as inflammation, immune response and cancer pathogenesis has been established. Finally, we highlight uninvestigated aspects of these two regulatory networks and address their potential as therapeutic targets

Renal sodium and magnesium reabsorption are not coupled in a mouse model of Gordon syndrome

Contains fulltext : 194422.pdf (publisher's version ) (Open Access

Dominant functional role of the novel phosphorylation site S811 in the human renal NaCl cotransporter

Contains fulltext : 194408.pdf (publisher's version ) (Closed access

Colonic expression of calcium transporter TRPV6 is regulated by dietary sodium butyrate.

Dietary fibers have been shown to increase the intestinal absorption of calcium (Ca(2+)) and magnesium (Mg(2+)). However, the mechanisms that explain the enhanced electrolyte absorption remain unknown. Therefore, this study aims to investigate the short-term and long-term effects of 5% (w/w) sodium butyrate (Na-butyrate), an important end-metabolite of bacterial fermentation of dietary fibers, on Ca(2+) and Mg(2+) homeostasis in mice. Serum Ca(2+) levels were only significantly increased in mice treated with Na-butyrate for 1 day. This was associated with a twofold increase in the mRNA expression levels of Trpv6 in the proximal and distal colon. Contrary, Na-butyrate did not affect serum Mg(2+) concentrations at either of the intervention periods. However, we observed a reduction in urinary Mg(2+) excretion, although not significantly, after 1 day of treatment. A significant reduction of 2.5-fold in urinary Mg(2+) excretion was observed after 14 days of treatment. Indeed, 14-day Na-butyrate supplementation increased colonic Trpm7 expression by 1.2-fold compared to control mice. In conclusion, short-term Na-butyrate supplementation increases serum Ca(2+) levels in mice. This was associated with increased mRNA expression levels of Trpv6 in the colon, suggesting that Na-butyrate regulates the expression of genes involved in active intestinal Ca(2+) absorption

New TRPM6 missense mutations linked to hypomagnesemia with secondary hypocalcemia.

Contains fulltext : 136379.pdf (publisher's version ) (Closed access)Despite recent progress in our understanding of renal magnesium (Mg(2+)) handling, the molecular mechanisms accounting for transepithelial Mg(2+) transport are still poorly understood. Mutations in the TRPM6 gene, encoding the epithelial Mg(2+) channel TRPM6 (transient receptor potential melastatin 6), have been proven to be the molecular cause of hypomagnesemia with secondary hypocalcemia (HSH; OMIM 602014). HSH manifests in the newborn period being characterized by very low serum Mg(2+) levels (<0.4 mmol/l) accompanied by low serum calcium (Ca(2+)) concentrations. A proportion of previously described TRPM6 mutations lead to a truncated TRPM6 protein resulting in a complete loss-of-function of the ion channel. In addition, five-point mutations have been previously described. The aim of this study was to complement the current clinical picture by adding the molecular data from five new missense mutations found in five patients with HSH. To this end, patch-clamp analysis and cell surface measurements were performed to assess the effect of the various mutations on TRPM6 channel function. All mutant channels, expressed in HEK293 cells, showed loss-of-function, whereas no severe trafficking impairment to the plasma membrane surface was observed. We conclude that the new TRPM6 missense mutations lead to dysregulated intestinal/renal Mg(2+) (re)absorption as a consequence of loss of TRPM6 channel function.1 april 201