Lack of functional wolframin causes drop in plasmalemmal sodium-calcium exchanger type 1 expression at early stage in rat model of Wolfram syndrome

Abstract

In previously introduced rat model of Wolfram syndrome, we have shown that in cardiac myocytes lacking functional wolframin protein the calcium transients and contractile response are significantly changed. Therefore, in this model, we evaluated protein and mRNA expression levels of following proteins involved in cardiac myocytes calcium homeostasis: the ryanodine receptor type 2, calsequestrin type 2, the junctophilin type 2 and plasmalemmal sodium-calcium exchanger type 1 (NCX1). For NCX1 we detected a significant decrease in expression both on protein and mRNA level. Thus, beyond its impact on endoplasmic reticulum stress, calcium, and mitochondria, wolframin influences processes in the myocyte plasma membrane.

The Expression of RAAS Key Receptors, Agtr2 and Bdkrb1, Is Downregulated at an Early Stage in a Rat Model of Wolfram Syndrome

“…Bradykinin is involved in inflammatory processes [65] and has been shown to induce BDKRB1-mediated Ca 2+ -dependent microglial migration in the CNS that relies on the reverse mode of sodium-calcium exchanger (NCX1) [36]. In the cardiomyocytes of WS rats, NCX1 is substantially downregulated [66]. Furthermore, after bradykinin stimulation, fibroblasts from WS patients release lower amounts of Ca 2+ from the ER compared to control samples [67], indicating the loss of bradykinin receptor sensitivity and NCX1 activity.…”

Cardiac Wolframinopathies: A Case Report of Myocarditis and a Literature Review of Cardiac Involvement in Wolfram Syndrome 1

“…Consistent with the impact of Wfs1 deficiency independently of diabetic phenotype, the duration of cytosolic calcium transients as well as the duration and amplitude of contractile response were significantly prolonged in the left ventricular myocytes freshly isolated from the hearts of a four-month-old euglycemic animal [ 26 ]. These perturbations were not associated with the expression of SERCA2 on the protein level, but there was a significant reduction in both protein and mRNA expression levels of plasmalemmal sodium–calcium exchanger type 1 (NCX1) [ 27 ]. Hence, aside from its effects on ER stress, calcium levels, and mitochondria, wolframin also influences activities within the plasma membrane of myocytes.…”