Type 1 ryanodine receptor knock-in mutation causing central core disease of skeletal muscle also displays a neuronal phenotype
Department of Microbiology and Physiological Systems; Biomedical Imaging Group
Medical Subject Headings
Ryanodine Receptor Calcium Release Channel
Life Sciences | Medicine and Health Sciences | Neuroscience and Neurobiology
The type 1 ryanodine receptor (RyR1) is expressed widely in the brain, with high levels in the cerebellum, hippocampus, and hypothalamus. We have shown that L-type Ca(2+) channels in terminals of hypothalamic magnocellular neurons are coupled to RyRs, as they are in skeletal muscle, allowing voltage-induced Ca(2+) release (VICaR) from internal Ca(2+) stores without Ca(2+) influx. Here we demonstrate that RyR1 plays a role in VICaR in nerve terminals. Furthermore, in heterozygotes from the Ryr1(I4895T/WT) (IT/+) mouse line, carrying a knock-in mutation corresponding to one that causes a severe form of human central core disease, VICaR is absent, demonstrating that type 1 RyR mediates VICaR and that these mice have a neuronal phenotype. The absence of VICaR was shown in two ways: first, depolarization in the absence of Ca(2+) influx elicited Ca(2+)syntillas (scintilla, spark, in a nerve terminal, a SYNaptic structure) in WT, but not in mutant terminals; second, in the presence of extracellular Ca(2+), IT/+ terminals showed a twofold decrease in global Ca(2+) transients, with no change in plasmalemmal Ca(2+) current. From these studies we draw two conclusions: (i) RyR1 plays a role in VICaR in hypothalamic nerve terminals; and (ii) a neuronal alteration accompanies the myopathy in IT/+ mice, and, possibly in humans carrying the corresponding RyR1 mutation.
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Citation: Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):610-5. Epub 2011 Dec 27. Link to article on publisher's site
DOI of Published Version
Proceedings of the National Academy of Sciences of the United States of America
De Crescenzo, Valerie; Fogarty, Kevin E.; Lefkowitz, Jason J.; Bellve, Karl D.; Zvaritch, Elena; MacLennan, David H.; and Walsh, John V. Jr., "Type 1 ryanodine receptor knock-in mutation causing central core disease of skeletal muscle also displays a neuronal phenotype" (2012). GSBS Student Publications. 1769.