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• W2077090675 abstract "Mutations in the smooth endoplasmic reticulum (sER) calcium channel Inositol Trisphosphate Receptor type 1 (IP3R1) in humans with the motor function coordination disorders Spinocerebellar Ataxia Types 15 and 16 (SCA15/16) and in a corresponding mouse model, the IP3R1delta18/delta18 mice, lead to reduced IP3R1 levels. We posit that increasing IP3R1 sensitivity to IP3 in ataxias with reduced IP3R1 could restore normal calcium response. On the other hand, in mouse models of the human polyglutamine (polyQ) ataxias, SCA2, and SCA3, the primary finding appears to be hyperactive IP3R1-mediated calcium release. It has been suggested that the polyQ SCA1 mice may also show hyperactive IP3R1. Yet, SCA1 mice show downregulated gene expression of IP3R1, Homer, metabotropic glutamate receptor (mGluR), smooth endoplasmic reticulum Ca-ATP-ase (SERCA), calbindin, parvalbumin, and other calcium signaling proteins. We create a computational model of pathological alterations in calcium signaling in cerebellar Purkinje neurons to investigate several forms of spinocerebellar ataxia associated with changes in the abundance, sensitivity, or activity of the calcium channel IP3R1. We find that increasing IP3R1 sensitivity to IP3 in computational models of SCA15/16 can restore normal calcium response if IP3R1 abundance is not too low. The studied range in IP3R1 levels reflects variability found in human and mouse ataxic models. Further, the required fold increases in sensitivity are within experimental ranges from experiments that use IP3R1 phosphorylation status to adjust its sensitivity to IP3. Results from our simulations of polyglutamine SCAs suggest that downregulation of some calcium signaling proteins may be partially compensatory. However, the downregulation of calcium buffer proteins observed in the SCA1 mice may contribute to pathology. Finally, our model suggests that the calcium-activated voltage-gated potassium channels may provide an important link between calcium metabolism and membrane potential in Purkinje cell function. Thus, we have established an initial platform for computational evaluation and prediction of ataxia pathophysiology. Specifically, the model has been used to investigate SCA15/16, SCA1, SCA2, and SCA3. Results suggest that experimental studies treating mouse models of any of these ataxias with appropriately chosen peptides resembling the C-terminal of IP3R1 could adjust receptor sensitivity, and thereby modulate calcium release and normalize IP3 response. In addition, the model supports the hypothesis of IP3R1 supersensitivity in SCA1." @default.
• W2077090675 created "2016-06-24" @default.
• W2077090675 creator A5019048997 @default.
• W2077090675 creator A5037186034 @default.
• W2077090675 date "2012-01-01" @default.
• W2077090675 modified "2023-09-25" @default.
• W2077090675 title "Computational analysis of calcium signaling and membrane electrophysiology in cerebellar Purkinje neurons associated with ataxia" @default.
• W2077090675 cites W100916699 @default.
• W2077090675 cites W1534586962 @default.
• W2077090675 cites W1585949905 @default.
• W2077090675 cites W1858802571 @default.
• W2077090675 cites W1966781482 @default.
• W2077090675 cites W1974850116 @default.
• W2077090675 cites W1974888639 @default.
• W2077090675 cites W1976949454 @default.
• W2077090675 cites W1979688001 @default.
• W2077090675 cites W1980069683 @default.
• W2077090675 cites W1982910974 @default.
• W2077090675 cites W1984916420 @default.
• W2077090675 cites W1993061512 @default.
• W2077090675 cites W1995140094 @default.
• W2077090675 cites W1997778815 @default.
• W2077090675 cites W1998828489 @default.
• W2077090675 cites W2001429889 @default.
• W2077090675 cites W2003945052 @default.
• W2077090675 cites W2006557034 @default.
• W2077090675 cites W2006656241 @default.
• W2077090675 cites W2012360559 @default.
• W2077090675 cites W2013029120 @default.
• W2077090675 cites W2015284446 @default.
• W2077090675 cites W2021549542 @default.
• W2077090675 cites W2022496032 @default.
• W2077090675 cites W2027560004 @default.
• W2077090675 cites W2031008134 @default.
• W2077090675 cites W2034963123 @default.
• W2077090675 cites W2040890820 @default.
• W2077090675 cites W2042166225 @default.
• W2077090675 cites W2043888873 @default.
• W2077090675 cites W2044663182 @default.
• W2077090675 cites W2045982871 @default.
• W2077090675 cites W2046440333 @default.
• W2077090675 cites W2048301742 @default.
• W2077090675 cites W2049445311 @default.
• W2077090675 cites W2049664820 @default.
• W2077090675 cites W2050996013 @default.
• W2077090675 cites W2053068031 @default.
• W2077090675 cites W2055194701 @default.
• W2077090675 cites W2057814921 @default.
• W2077090675 cites W2062744504 @default.
• W2077090675 cites W2064551580 @default.
• W2077090675 cites W2065528657 @default.
• W2077090675 cites W2066022578 @default.
• W2077090675 cites W2066261176 @default.
• W2077090675 cites W2066536601 @default.
• W2077090675 cites W2067144876 @default.
• W2077090675 cites W2068505134 @default.
• W2077090675 cites W2070053976 @default.
• W2077090675 cites W2074890054 @default.
• W2077090675 cites W2075681146 @default.
• W2077090675 cites W2080229778 @default.
• W2077090675 cites W2086332328 @default.
• W2077090675 cites W2086858480 @default.
• W2077090675 cites W2087530259 @default.
• W2077090675 cites W2092371719 @default.
• W2077090675 cites W2092762531 @default.
• W2077090675 cites W2093566872 @default.
• W2077090675 cites W2102459791 @default.
• W2077090675 cites W2110540970 @default.
• W2077090675 cites W2113019718 @default.
• W2077090675 cites W2114632792 @default.
• W2077090675 cites W2115807468 @default.
• W2077090675 cites W2119100472 @default.
• W2077090675 cites W2120600363 @default.
• W2077090675 cites W2121735882 @default.
• W2077090675 cites W2122916910 @default.
• W2077090675 cites W2123831527 @default.
• W2077090675 cites W2133485291 @default.
• W2077090675 cites W2135313225 @default.
• W2077090675 cites W2137632894 @default.
• W2077090675 cites W2138768371 @default.
• W2077090675 cites W2146488942 @default.
• W2077090675 cites W2148269081 @default.
• W2077090675 cites W2154778779 @default.
• W2077090675 cites W2157990975 @default.
• W2077090675 cites W2159714739 @default.
• W2077090675 cites W2163191890 @default.
• W2077090675 cites W2171629223 @default.
• W2077090675 cites W2255469197 @default.
• W2077090675 cites W2325787268 @default.
• W2077090675 cites W2918062993 @default.
• W2077090675 cites W31938543 @default.
• W2077090675 cites W4229707532 @default.
• W2077090675 doi "https://doi.org/10.1186/1752-0509-6-70" @default.
• W2077090675 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3468360" @default.
• W2077090675 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/22703638" @default.
• W2077090675 hasPublicationYear "2012" @default.
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