CaMKIIα hub ligands are unable to reverse known phenotypes in Angelman syndrome mice
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00603644" target="_blank" >RIV/61388963:_____/25:00603644 - isvavai.cz</a>
Result on the web
<a href="https://doi.org/10.1111/bcpt.14112" target="_blank" >https://doi.org/10.1111/bcpt.14112</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1111/bcpt.14112" target="_blank" >10.1111/bcpt.14112</a>
Alternative languages
Result language
angličtina
Original language name
CaMKIIα hub ligands are unable to reverse known phenotypes in Angelman syndrome mice
Original language description
Angelman Syndrome (AS) is a neurodevelopmental disorder caused by the loss of function of ubiquitin-protein ligase E3A (UBE3A), resulting in marked changes in synaptic plasticity. In AS mice, a dysregulation of Ca2+/calmodulin-dependent protein kinase II alpha (CaMKII alpha) was previously described. This has been convincingly validated through genetic rescue of prominent phenotypes in mouse cross-breeding experiments. Selective ligands that specifically stabilize the CaMKII alpha central association (hub) domain and affect different conformational states in vitro are now available. Two of these ligands, 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) and (E)-2-(5-hydroxy-2-phenyl-5,7,8,9-tetrahydro-6H-benzo[7]annulen-6-ylidene)acetic acid (Ph-HTBA), confer neuroprotection after ischemic stroke in mice where CaMKII alpha is known to be dysregulated. Here, we sought to investigate whether pharmacological modulation with these prototypical CaMKII alpha hub ligands presents a viable approach to alleviate AS symptoms. We performed an in vivo functional evaluation of AS mice treated for a total of 14 days with either HOCPCA or Ph-HTBA (7 days pre-treatment and 7 days of behavioural assessment). Both compounds were well-tolerated but unable to revert robust phenotypes of motor performance, anxiety, repetitive behaviour or seizures in AS mice. Biochemical experiments subsequently assessed CaMKII alpha autophosphorylation in AS mouse brain tissue. Taken together our results indicate that pharmacological modulation of CaMKII alpha via the selective hub ligands used here is not a viable treatment strategy in AS.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10406 - Analytical chemistry
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Basic & Clinical Pharmacology & Toxicology
ISSN
1742-7835
e-ISSN
1742-7843
Volume of the periodical
136
Issue of the periodical within the volume
1
Country of publishing house
US - UNITED STATES
Number of pages
13
Pages from-to
e14112
UT code for WoS article
001388144900022
EID of the result in the Scopus database
2-s2.0-85211614839