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Magnesium homeostasis
Published in Kupetsky A. Erine, Magnesium, 2019
Ravi Sunderkrishnan, Maria P. Martinez Cantarin
Chronic metabolic acidosis reduces the renal TRPM6 expression in the apical membrane of the distal convoluted tubule, causing hypermagnesuria and thus hypomagnesemia. Conversely, chronic metabolic alkalosis causes an upregulation of TRPM6 expression, leading to hypermagnesemia.18
Ion Channels in Immune Cells
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Devasena Ponnalagu, Shridhar Sanghvi, Shyam S. Bansal, Harpreet Singh
TRP channels are present in both the adaptive and the innate immune cells and act as mediators to conduct Ca2+, Mg2+ (TRPM2, TRPM6, TRPM7), and Na+ (TRPM4). As described earlier, the major role of some of the TRP channels is to modulate intracellular Ca2+ in immune cells and, thus, influence their function. They have been established to play a role in phagocytosis, immune cell migration, and the release of inflammatory cytokines. It is known that, following TCR stimulation, TRPM2 channels become activated probably via release of cyclic ADP ribose (ADPR) from the ER, which is involved in their proliferation and pro-inflammatory cytokine secretion59,60. Moreover, TRPM2 deficiency mitigated the development of encephalomyelitis in mice61. TRPM2-mediated Ca2+ signaling was also shown to be involved in the maturation of DCs through modulation of the processing of MHC class II molecules62. The absence of TRPM4 channels in DCs led to impaired migration due to disruption of Ca2+ homeostasis60. In addition, phagocytic activity and cytokine release by macrophages were diminished in TRPM4-deficient mice60. B cells lacking a TRPM7 channel exhibited an inability to proliferate and an increased death rate60. In the case of T cells as well, mice lacking T cell–specific TRPM7 showed a defect in T cell development60. There are also other members of this channel group that have been studied extensively and shown to be important in modulating immune cell function and development and inflammatory diseases60. Due to their key role in immune cell maturation and activation, they are also considered to be a great therapeutic target against autoimmune disorders, like rheumatoid arthritis, type I diabetes, lupus erythematosus, and multiple sclerosis, and thus need to be evaluated clinically.
Ion Channel Conformational Coupling in Ischemic Neuronal Death
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
TRP channels represent a large group of non-selective cation channels conducting not only monovalent cations such as Na+ and K+, but also divalent cations like Ca2+, Zn2+, or Mg2+ to different degrees (Nilius and Owsianik, 2011). The 28 mammalian TRP members are divided into six subfamilies and involved in diverse functions such as sensing temperature, osmotic pressure, or volume changes, and a variety of chemicals (Ramsey et al., 2006). TRP channels play important roles in many physical and pathological processes, such as taste, nociception, and ischemic injuries. Although most TRP channels fulfill their functions by regulating ionic balance across biomembranes, some of them, such as transient receptor potential-melastatin-like 2 (TRPM2), TRPM6, and TRPM7, also function in ion conduction-independent manners (Krapivinsky et al., 2014; Perraud et al., 2001; Riazanova et al., 2001; Runnels et al., 2001; Sano et al., 2001). For instance, TRPM6 and TRPM7 are chanzymes, which not only act as ion channels mediating cation fluxes including Ca2+, Zn2+, and Mg2+, but also contain a serine/threonine kinase domain at the carboxyl terminus (CT) of each subunit. TRPM7 has been considered as a major regulator for cellular Mg2+ homeostasis in vertebrates. However, tissue-specific deletion of the Trpm7 gene from mouse T cells impairs thymopoiesis without affecting either the acute Mg2+ uptake ability or the maintenance of cellular Mg2+ levels (Jin et al., 2008). Instead, syntheses of many essential growth factors are severely disrupted in Trpm7−/− thymocytes, which impairs the differentiation and maintenance of thymic epithelial cells. Therefore, TRPM7 regulates thymopoiesis through its CT kinase activity but not via Mg2+ conducting function. Interestingly, in some specific progenitors derived from mouse embryonic stem cells (mESCs), the TRPM7 kinase domain can be cleaved from the channel part in vivo in a cell type-specific fashion (Krapivinsky et al., 2014). The TRPM7 cleaved kinases (M7CKs) translocate to the nucleus and bind to the zinc-finger domains of multiple chromatin-remodeling complexes, which modify histone phosphorylation (e.g. H3S10, H3S28, and H3T3) to regulate gene expression pattern. This binding is Zn2+ dependent and largely dependent on TRPM7’s Zn2+ conducting function, suggesting a synergistic action of the ionotropic and metabotropic functions of TRPM7. The cleavage-dependent nuclear action of TRPM7 resembles that of Cav1.2 L-type voltage-gated Ca2+ channel, which also regulates gene expression through proteolytic cleavage of its CT and translocation of the cleaved small fragment into nucleus to activate gene transcription in neurons (Gomez-Ospina et al., 2006).
Investigational drugs in early phase clinical trials targeting thermotransient receptor potential (thermoTRP) channels
Published in Expert Opinion on Investigational Drugs, 2020
Asia Fernández-Carvajal, Rosario González-Muñiz, Gregorio Fernández-Ballester, Antonio Ferrer-Montiel
Another important family within the TRP ion channel superfamily is the transient receptor potential melastatin (TRPM) receptors, composed of eight members. They can be subdivided into four groups, based on structural homology: TRPM1 and 3, TRPM4-5, TRPM6-7, and TRPM2 and 8 [55]. Most of these plasma membrane ion channels are nonselective Ca2+-permeable (TRPM1-3 and TRPM6-8), while TRPM4/5 are Ca2+-impermeable. In addition, TRPM6-7 are Mg2+-permeable and involved in mammalian Mg2+ homeostasis [56]. TRPM members are differently expressed in many tissues, including primary sensory neurons (TRPM3, TRPM8), prostate (TRPM8), pancreatic β–cells (TRPM2, TRPM3, TRPM5), retina cells (TRPM1), kidney (TRPM6), liver, and heart (TRPM4), among others [57]. Unlike the other TRP channels, TRPM channels lack the N-terminal ankyrin repeats.
Increased risk of post-stroke epilepsy in Chinese patients with a TRPM6 polymorphism
Published in Neurological Research, 2019
Chuan-Yi Fu, Shui-Jie Chen, Nan-Hua Cai, Zhao-Hui Liu, Mao Zhang, Peng-Cheng Wang, Jian-Nong Zhao
Melastatin-related transient receptor potential ion channel (TRPM) proteins comprise a family of non-selective cation channels that may be divided into eight types according to their structural homology [11]. TRPM6 (official name: transient receptor potential cation channel subfamily M member 6) acts mainly as a Mg2+ transport regulator. Mutations in the gene that encodes TRPM6 (i.e., TRPM6) can result in abnormal Mg2+ transport in intestinal and renal tubule epithelia, leading to hypercalcemia or hypocalcemia [12]. Trpm6 deficiency can lead to embryo death, neural tube malformation, and reduced serum Mg2+ concentrations in mice, and a magnesium-rich diet can reverse mortality in such mice [13]. The beneficial effect of magnesium supplementation may result from the activation of sodium/potassium ion-ATP enzymes and the subsequent increase in the concentration of intracellular potassium. Moreover, increased magnesium levels lead to reduced sodium levels in cells, which in turn inhibit sodium/calcium exchange and maintain relatively low intracellular Ca2+ levels in the cell membrane, thereby avoiding Ca2+ overload.
Hypomagnesemia and hypermagnesemia
Published in Acta Clinica Belgica, 2019
The recommended daily intake of magnesium is 320 and 420 mg for adult women and men, respectively [1]. Absorption mainly (80–90%) occurs through paracellular concentration-driven passive uptake of magnesium in the jejunum and colon and to a minor degree by active transcellular transport across the magnesium absorbing channels transient receptor of melastatin (TRPM) 6 and 7) in the colon [1]. Active absorption increases in hypomagnesemia but, unlike passive absorption, is saturable with increasing magnesium intake. Intestinal absorption of magnesium is enhanced by active vitamin D. The majority of the filtered magnesium load in the kidney is reabsorbed in the thin ascending limb of Henle (70%) across tight junction channels, whereas the remainder occurs at the level of the proximal tubule (10–25%) and in the distal collecting tubule (DCT) through active absorption via TRMP6 [1]. Fine-tuning of the magnesium balance by regulating the final urinary magnesium excretion occurs particularly at the level of the DCT. Upon lower magnesium intake, intestinal absorption can increase from 40% to 80% while fractional urinary magnesium excretion decreases to 0.5%. Magnesium homeostasis can be dysregulated by disease conditions or drugs interfering with intestinal and/or renal magnesium absorption, whereby some drugs such as EGFR-inhibitors cetuximab and cisplatinum downregulate the expression of TRPM6 at the DCT. Etiologies of hypomagnesemia are summarized in Table 1. Also, calcineurin inhibitors cyclosporine and especially tacrolimus induce enhanced renal magnesium wasting through dose-dependent inhibition of TRPM6 expression in the DCT [1,12]. This leads to mild or moderate hypomagnesemia (0.5–0.7 mM) in about 50% of recipients the first weeks and months after transplantation [12]. PPI impair the adaptive increase in intestinal magnesium absorption by inhibiting TRPM6/7, resulting in hypomagnesemia of variable severity [4]. Not only resins but also new-generation potassium binders such as patiromer contribute to the development of hypomagnesemia [13]. Also, proteinuria leads to renal magnesium wasting and predicts a lower increment of serum magnesium concentration upon magnesium supplementation [14].