Transient receptor potential melastatin 2 (TRPM2) is a ligand-gated Ca-permeable nonselective cation channel. Whereas physiological stimuli, such as chemotactic agents, evoke controlled Ca signals via TRPM2, pathophysiological stimuli such as reactive oxygen species and genotoxic stress result in prolonged TRPM2-mediated Ca entry and, consequently, apoptosis. To date, adenosine 5'-diphosphoribose (ADPR) has been assumed to be the main agonist for TRPM2. Here we show that 2'-deoxy-ADPR was a significantly better TRPM2 agonist, inducing 10.4-fold higher whole-cell currents at saturation. Mechanistically, this increased activity was caused by a decreased rate of inactivation and higher average open probability. Using high-performance liquid chromatography (HPLC) and mass spectrometry, we detected endogenous 2'-deoxy-ADPR in Jurkat T lymphocytes. Consistently, cytosolic nicotinamide mononucleotide adenylyltransferase 2 (NMNAT-2) and nicotinamide adenine dinucleotide (NAD)-glycohydrolase CD38 sequentially catalyzed the synthesis of 2'-deoxy-ADPR from nicotinamide mononucleotide (NMN) and 2'-deoxy-ATP in vitro. Thus, 2'-deoxy-ADPR is an endogenous TRPM2 superagonist that may act as a cell signaling molecule.
Children with congenital heart disease need adequate diagnostic classification regarding their cardiovascular status (CVS). N-terminal brain natriuretic peptide (N-BNP) plasma concentration indicates dysfunction of the cardiovascular system and guides decisions concerning treatment and prognosis. Reference values are established for adults, with age-dependent increasing values and higher values in women. To avoid misclassification concerning the CVS, a large group of healthy children and adolescents can be used show the relationship between gender, age, and N-BNP and these can serve as reference values. N-BNP was measured in 434 healthy subjects (240 female and 194 male) with ages ranging from 0 to 32 years without any cardiovascular disease or renal or hepatic impairment. Measurements were performed with an electrochemiluminescence immunoassay from Roche Diagnostics. Mean N-BNP decreased from 12.6 fmol/ml (0-9 years; n = 79) to 9.41 fmol/ml (10-14 years; n = 154) and in adolescents from 6.1 (15-19 years; n = 99) to 4.8 fmol/ml (> 19 years; n = 102) in adults (p < 0.05). Mean N-BNP concerning gender did not differ in any age group younger than 19 years. In contrast, the adult female group had 78% higher N-BNP compared to the male group (p < 0.05). There was a significant peak in N-BNP at the age of 12-14 years. This study shows that reference values for N-BNP differed profoundly in children compared to adults and were up to 260% higher in children without any gender difference. Therefore, these reference values will help to avoid CVS misclassification in children for the biomarker N-BNP.
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