Novel Aspects of Renal Magnesium Homeostasis

Abstract

Magnesium (Mg2+) is indispensable for several vital functions, such as neurotransmission, cardiac conductance, blood glucose, blood pressure regulation, and proper function of more than 300 enzymes. Thus, Mg2+ homeostasis is subject to tight regulation. Besides the fast and immediate regulation of plasma Mg2+, a major part of Mg2+ homeostasis is realized by a concerted action of epithelial molecular structures that tightly control intestinal uptake and renal absorption. This mechanism is provided by a combination of para- and transcellular pathways. Whereas the first pathway provides the organism with a maximal amount of vital substances by a minimal energy expenditure, the latter enables controlling and fine-tuning by means of local and regional regulatory systems and also, hormonal control. The paracellular pathway is driven by an electrochemical gradient and realized in principal by the tight junction (TJ), a supramolecular organization of membrane-bound proteins and their adaptor and scaffolding proteins. TJ determinants are claudins (CLDN), a family of membrane spanning proteins that generate a barrier or a pore between two adjacent epithelial cells. Many insights into molecular mechanisms of Mg2+ handling have been achieved by the identification of alterations and mutations in human genes which cause disorders of paracellular Mg2+ pathways (CLDN10, CLDN14, CLDN16, CLDN19). Also, in the distal convoluted tubule, a basolateral protein, CNNM2, causes if mutated, familial dominant and also recessive renal Mg2+ wasting, albeit its true function has not been clarified yet, but is assumed to play a key role in the transcellular pathway. Moreover, mutations in human genes that are involved in regulating these proteins directly or indirectly cause, if mutated human diseases, mostly in combination with comorbidities as diabetes, cystic renal disease, or metabolic abnormalities. Generation and characterization of animal models harboring the corresponding mutations have further contributed to the elucidation of physiology and pathophysiology of Mg2+ disorders. Finally, high-end crystallization techniques allow understanding of Mg2+ handling in more detail. As this field is rapidly growing, we describe here the principles of physiology and pathophysiology of epithelial transport of renal Mg2+ homeostasis with emphasis on recently identified mechanisms involved.

Structural basis for the Mg 2+ recognition and regulation of the CorC Mg 2+ transporter

“…In humans, Mg 2+ is involved in the maintenance of heart rhythm, blood pressure, neuromuscular conduction, bone integrity, and glucose metabolism (4). Accordingly, cellular imbalance of Mg 2+ homeostasis is associated with multiple diseases (4), and Mg 2+ transport proteins play a primary role in homeostasis (5,6).…”

Current Structural Knowledge on the CNNM Family of Magnesium Transport Mediators

“…Considering its biological relevance, our body relies on complex molecular systems that ensure the bioavailability of this cation by establishing a careful balance between its absorption and excretion [ 9 ]. These processes were recently reviewed in detail [ 8 , 10 ]. However, the exact mechanisms by which the different channels, transporters, and sensors facilitate the passing of Mg 2+ through the cell membranes remains poorly understood [ 11 ].…”

Oral Magnesium Supplementation Ameliorates Glucose Tolerance in Streptozotocin-Nicotinamide Induced Diabetic Rats

“…Magnesium is one of the essential mineral elements of significant advantage in the human body system. It aids the activity of many metabolic pathways including protein synthesis and DNA production, it acts as a cofactor of various metabolic enzymes and also activates various signaling pathways in the body system [Gimenez-Mascarell et al, 2018;Grober et al, 2015;Costello et al, 2016;de Baaij et al, 2015;Morakinyo et al, 2018;Solaimani et al, 2014].…”