Hypomagnesemia with Secondary Hypoparathyroidism and Hypocalcemia due to Novel Variants in the Transient Receptor Potential Cation Channel Subfamily M Member 6 (TRPM6) Gene

2021 ◽  
Author(s):  
Geetanjali Jain ◽  
Gourab Das ◽  
Rakhi Malhotra ◽  
Sateesh Ramchandran ◽  
Nagaraja M. Phani ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Autosomal Recessive Disorder ◽  
Cation Channel ◽  
Neonatal Seizures ◽  
Rare Autosomal Recessive Disorder ◽  
Novel Variants ◽  
Transient Receptor ◽  
Trpm6 Gene

AbstractHOMG1 (hypomagnesemia 1, intestinal) or hypomagnesemia with secondary hypocalcemia is a rare autosomal recessive disorder of magnesium metabolism, characterized by impaired magnesium absorption. This disorder may mimic other conditions presenting with neonatal seizures. Here, we report an infant diagnosed to have hypomagnesemia with secondary hypocalcemia due to novel variants in TRPM6 gene.

scholarly journals Two Decades of Evolution of Our Understanding of the Transient Receptor Potential Melastatin 2 (TRPM2) Cation Channel

Life ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 397
Author(s):  
Andras Szollosi
Keyword(s):  
Structure Function ◽  
Cell Activation ◽  
Transient Receptor Potential ◽  
Immune Cell ◽  
Receptor Potential ◽  
Cation Channel ◽  
Biophysical Properties ◽  
Vast Number ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

The transient receptor potential melastatin (TRPM) family belongs to the superfamily of TRP ion channels. It consists of eight family members that are involved in a plethora of cellular functions. TRPM2 is a homotetrameric Ca2+-permeable cation channel activated upon oxidative stress and is important, among others, for body heat control, immune cell activation and insulin secretion. Invertebrate TRPM2 proteins are channel enzymes; they hydrolyze the activating ligand, ADP-ribose, which is likely important for functional regulation. Since its cloning in 1998, the understanding of the biophysical properties of the channel has greatly advanced due to a vast number of structure–function studies. The physiological regulators of the channel have been identified and characterized in cell-free systems. In the wake of the recent structural biochemistry revolution, several TRPM2 cryo-EM structures have been published. These structures have helped to understand the general features of the channel, but at the same time have revealed unexplained mechanistic differences among channel orthologues. The present review aims at depicting the major research lines in TRPM2 structure-function. It discusses biophysical properties of the pore and the mode of action of direct channel effectors, and interprets these functional properties on the basis of recent three-dimensional structural models.

scholarly journals The proposed channel-enzyme transient receptor potential melastatin 2 does not possess ADP ribose hydrolase activity

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Iordan Iordanov ◽  
Csaba Mihályi ◽  
Balázs Tóth ◽  
László Csanády
Keyword(s):  
Cell Death ◽  
Insulin Secretion ◽  
Transient Receptor Potential ◽  
Channel Gating ◽  
Receptor Potential ◽  
Cation Channel ◽  
Chimeric Proteins ◽  
Transient Receptor Potential Melastatin ◽  
Biochemical Studies ◽  
Transient Receptor

Transient Receptor Potential Melastatin 2 (TRPM2) is a Ca2+-permeable cation channel essential for immunocyte activation, insulin secretion, and postischemic cell death. TRPM2 is activated by ADP ribose (ADPR) binding to its C-terminal cytosolic NUDT9-homology (NUDT9H) domain, homologous to the soluble mitochondrial ADPR pyrophosphatase (ADPRase) NUDT9. Reported ADPR hydrolysis classified TRPM2 as a channel-enzyme, but insolubility of isolated NUDT9H hampered further investigations. Here we developed a soluble NUDT9H model using chimeric proteins built from complementary polypeptide fragments of NUDT9H and NUDT9. When expressed in E.coli, chimeras containing up to ~90% NUDT9H sequence remained soluble and were affinity-purified. In ADPRase assays the conserved Nudix-box sequence of NUDT9 proved essential for activity (kcat~4-9s-1), that of NUDT9H did not support catalysis. Replacing NUDT9H in full-length TRPM2 with soluble chimeras retained ADPR-dependent channel gating (K1/2~1-5 μM), confirming functionality of chimeric domains. Thus, TRPM2 is not a 'chanzyme'. Chimeras provide convenient soluble NUDT9H models for structural/biochemical studies.

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