Voltage-gated calcium fluxes studied in skeletal muscle fibers of genetically engineered mice
Auch gedruckt in der BibliothekZ: J-H 13.218; W: W-H 11.662
LizenzStandard (Fassung vom 01.10.2008)
Ca2+ channels play central roles in cellular signaling. In skeletal muscle, the dihydropyridine receptors (DHPRs), L-type Ca2+ channels, play a pivotal role as voltage sensors for the remote control of type 1 ryanodine receptors (RyR1). The general aim of this study was to characterize the alterations of voltage controlled fluxes of Ca2+ entry and Ca2+ release from internal stores in fully differentiated skeletal muscle fibers of normal and genetically modified mice. The first goal was to investigate the cross influence of the skeletal muscle-specific gamma1 subunit of the DHPR and of the PAA Ca2+ antagonist (-)D888. For this purpose, I studied voltage-dependent gating of both L-type Ca2+ current and Ca2+ release in muscle fibers of wildtype and gamma1 knock-out mice. The results indicate a common mechanism of modulation of voltage-dependent inactivation and suggest that the gamma1-subunit acts as an endogenous calcium antagonist. The second goal of the study was to assess the functional consequences of the Y522S MH mutation in RyR1 to EC coupling in adult skeletal muscle and to define the mechanisms that limit leakage of Ca2+ from the SR. For this purpose a recently developed transgenic mouse heterozygous for the RyR1 mutation was used. The investigations were focused on changes in the voltage window of Ca2+ flux generated by the overlap region of activation and inactivation curves, which likely contribute to the pathology. The results of this part of the study show evidence of a novel feedback mechanism that partially compensates for the tendency of the mutation to increase window Ca2+ flux. The findings provide useful information and are important for understanding the normal/dysfunctional Ca2+ handling in skeletal muscle of mammalian organism and can, therefore, be relevant to human muscle physiology.
Erstellung / Fertigstellung
Normierte SchlagwörterCalciumkanal [GND]
Malignant hyperthermia [MeSH]