The role of kinase-coupled channel TRPM6 in cardiac automaticity

Stadlbauer, Benjamin (2023): The role of kinase-coupled channel TRPM6 in cardiac automaticity. Dissertation, LMU München: Medizinische Fakultät

Abstract

TRPM6 and TRPM7 are unique proteins comprising an ion channel and kinase domain. The TRPM6 and TRPM7 channels are permeable for Mg2+ and play a crucial role in whole-body Mg2+ homeostasis. TRPM7 is expressed ubiquitously, while the expression of TRPM6 is limited to the kidney, intestine, lung, heart and testis. In humans, TRPM6 mutation causes Hypomagnesemia with Secondary Hypocalcemia (HSH). While HSH patients primarily present with seizures the symptoms also include cardiomyopathy and arrhythmia. Experiments with Trpm6 gene-deficient mice led to the hypothesis that hypomagnesemia in HSH patients was primarily caused by impaired intestinal transport of Mg2+. While the physiological role of TRPM6 in the intestine is relatively well defined, its function in the cardiovascular system remains to be established. In the present study, we used in situ hybridization (ISH) and qRT-PCR approaches to examine the expression of Trpm6 in the murine heart. We found that Trpm6 transcripts are abundantly present in cardiomyocytes of the embryonic heart and the heart of adult animals. To investigate the physiological role of TRPM6, we conducted non-invasive ECG measurements in freely moving mice. We observed that 4-week-old Trpm6 null mice develop sinus tachycardia and display a shortened heart rate corrected QT interval when compared to their control littermates. Furthermore, we found that dietary Mg2+ supplementation of pregnant females normalized both the elevated heart rate, as well as the shortened corrected QT interval in Trpm6 null pups. However, a delayed Mg2+-enriched diet provided only after the weaning stage was inefficient in normalizing the increased heart rate, suggesting that Mg2+ deficiency during prenatal development and weaning caused sinus tachycardia. Next, we analyzed the heart transcriptome using the gene microarray approach. We found that the expression levels of genes coding for G protein-coupled receptor kinase 2 (Grk2), myosin heavy chain 14 (Myh14) and Ras-Related Protein Rab-4A (Rab4A) were reduced in the heart of 8-week-old Trpm6 null mice, suggesting altered beta-adrenergic signaling within the sinus node as one potential mechanism behind the tachycardia. Collectively, our results suggest that Trpm6 is expressed in cardiomyocytes and that Trpm6 null mice develop a defect in the regulation of the heart rhythm caused by Mg2+ deficiency. Hence, ECG monitoring should be performed in human patients suffering from inherited or acquired forms of hypomagnesemia in order to find and treat accompanying cardiac arrhythmia.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 25. Mai 2023
• 1. Bericht­erstatter:in: Gudermann, Thomas