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《第十一届全国钙信号和细胞功能研讨会摘要集》2016年
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RYR1 mutations affect Ca~(2+) signaling in vascular smooth muscle cells

Ruben Lopez  Heinz Jungbluth  Francesco Zorzato  Susan Treves  
【摘要】:Smooth muscle cells exhibit a complex intracellular calcium regulation, expressing both Ins P3 R and Ry R calcium channels.While investigating mice knocked in for the gain of function RYR1 Y522 S mutation, causative of Malignant Hyperthermia(MH RYR1Y522 S knock in mice), we observed that the mice exhibited an abnormally long bleeding phenotype. Wepostulated that this could be caused by an alteration of vascular smooth muscle cell functionbrought about by the RYR1 mutation. Detailed examination of the bleeding times in mice and in patients carrying gain of function RYR1 mutations showed that(i)bleeding times in the MH RYR1Y522 S knock in mice were 3 times longer compared to those of wild type littermates,(ii) 8/21 RYR1 mutated patients had abnormal bleeding scores compared to 0/14 controls. Interestingly, the bleeding defect of mice and of one patient could be reversed by dantrolene, a clinically used Ry R1 antagonist. To gain insight into themechanism bringing about this phenotype, we investigated the role of Ry R1 in primary vascular smooth muscle cellsisolated from tail arteries of wild type and RYR1Y522 S knock-in mice. Cells isolated from mutant mice exhibit a higher frequency of subplasmalemmal Ca~(2+) sparks leading to a more negative resting membrane potential. The effect on the membrane potential is consistent with vasodilation leading to prolonged bleeding times. Our results provide proof of principle evidence that blocking abnormal Ry R1 function with pharmaceutical compounds such as dantrolene could be of therapeutic value in the treatment of such bleeding disorders.
【作者单位】:Departments of Anesthesia and Biomedicine, Basel University Hospital Department of Paediatric Neurology, Neuromuscular Service, Evelina Children's Hospital, St Thomas' Hospital Department of Life Sciences, General Pathology Section, University of Ferrara
【分类号】:R965
【正文快照】:
RYR1 mutations affect Ca~(2+) signaling in vascular smooth muscle cells@Ruben Lopez$Departments of Anesthesia and Biomedicine, Basel University Hospital!Basel, Switzerland @Heinz Jungbluth$Department of Paediatric Neurology, Neuromuscular Service, Evel

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