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Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin-dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology
Pathological loss-of-function mutations in cyclin-dependent kinase-like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disorder associated with severe and medically refractory early-life epilepsy, motor, cognitive, visual, and autonomic disturbances in the abse...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10406435/ https://www.ncbi.nlm.nih.gov/pubmed/37490324 http://dx.doi.org/10.7554/eLife.88206 |
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author | Castano, Anna Silvestre, Margaux Wells, Carrow I Sanderson, Jennifer L Ferrer, Carla A Ong, Han Wee Lang, Yi Richardson, William Silvaroli, Josie A Bashore, Frances M Smith, Jeffery L Genereux, Isabelle M Dempster, Kelvin Drewry, David H Pabla, Navlot S Bullock, Alex N Benke, Tim A Ultanir, Sila K Axtman, Alison D |
author_facet | Castano, Anna Silvestre, Margaux Wells, Carrow I Sanderson, Jennifer L Ferrer, Carla A Ong, Han Wee Lang, Yi Richardson, William Silvaroli, Josie A Bashore, Frances M Smith, Jeffery L Genereux, Isabelle M Dempster, Kelvin Drewry, David H Pabla, Navlot S Bullock, Alex N Benke, Tim A Ultanir, Sila K Axtman, Alison D |
author_sort | Castano, Anna |
collection | PubMed |
description | Pathological loss-of-function mutations in cyclin-dependent kinase-like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disorder associated with severe and medically refractory early-life epilepsy, motor, cognitive, visual, and autonomic disturbances in the absence of any structural brain pathology. Analysis of genetic variants in CDD has indicated that CDKL5 kinase function is central to disease pathology. CDKL5 encodes a serine-threonine kinase with significant homology to GSK3β, which has also been linked to synaptic function. Further, Cdkl5 knock-out rodents have increased GSK3β activity and often increased long-term potentiation (LTP). Thus, development of a specific CDKL5 inhibitor must be careful to exclude cross-talk with GSK3β activity. We synthesized and characterized specific, high-affinity inhibitors of CDKL5 that do not have detectable activity for GSK3β. These compounds are very soluble in water but blood–brain barrier penetration is low. In rat hippocampal brain slices, acute inhibition of CDKL5 selectively reduces postsynaptic function of AMPA-type glutamate receptors in a dose-dependent manner. Acute inhibition of CDKL5 reduces hippocampal LTP. These studies provide new tools and insights into the role of CDKL5 as a newly appreciated key kinase necessary for synaptic plasticity. Comparisons to rodent knock-out studies suggest that compensatory changes have limited the understanding of the roles of CDKL5 in synaptic physiology, plasticity, and human neuropathology. |
format | Online Article Text |
id | pubmed-10406435 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-104064352023-08-08 Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin-dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology Castano, Anna Silvestre, Margaux Wells, Carrow I Sanderson, Jennifer L Ferrer, Carla A Ong, Han Wee Lang, Yi Richardson, William Silvaroli, Josie A Bashore, Frances M Smith, Jeffery L Genereux, Isabelle M Dempster, Kelvin Drewry, David H Pabla, Navlot S Bullock, Alex N Benke, Tim A Ultanir, Sila K Axtman, Alison D eLife Neuroscience Pathological loss-of-function mutations in cyclin-dependent kinase-like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disorder associated with severe and medically refractory early-life epilepsy, motor, cognitive, visual, and autonomic disturbances in the absence of any structural brain pathology. Analysis of genetic variants in CDD has indicated that CDKL5 kinase function is central to disease pathology. CDKL5 encodes a serine-threonine kinase with significant homology to GSK3β, which has also been linked to synaptic function. Further, Cdkl5 knock-out rodents have increased GSK3β activity and often increased long-term potentiation (LTP). Thus, development of a specific CDKL5 inhibitor must be careful to exclude cross-talk with GSK3β activity. We synthesized and characterized specific, high-affinity inhibitors of CDKL5 that do not have detectable activity for GSK3β. These compounds are very soluble in water but blood–brain barrier penetration is low. In rat hippocampal brain slices, acute inhibition of CDKL5 selectively reduces postsynaptic function of AMPA-type glutamate receptors in a dose-dependent manner. Acute inhibition of CDKL5 reduces hippocampal LTP. These studies provide new tools and insights into the role of CDKL5 as a newly appreciated key kinase necessary for synaptic plasticity. Comparisons to rodent knock-out studies suggest that compensatory changes have limited the understanding of the roles of CDKL5 in synaptic physiology, plasticity, and human neuropathology. eLife Sciences Publications, Ltd 2023-07-25 /pmc/articles/PMC10406435/ /pubmed/37490324 http://dx.doi.org/10.7554/eLife.88206 Text en © 2023, Castano, Silvestre et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Neuroscience Castano, Anna Silvestre, Margaux Wells, Carrow I Sanderson, Jennifer L Ferrer, Carla A Ong, Han Wee Lang, Yi Richardson, William Silvaroli, Josie A Bashore, Frances M Smith, Jeffery L Genereux, Isabelle M Dempster, Kelvin Drewry, David H Pabla, Navlot S Bullock, Alex N Benke, Tim A Ultanir, Sila K Axtman, Alison D Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin-dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology |
title | Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin-dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology |
title_full | Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin-dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology |
title_fullStr | Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin-dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology |
title_full_unstemmed | Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin-dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology |
title_short | Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin-dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology |
title_sort | discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin-dependent kinase-like 5 (cdkl5) demonstrates role in hippocampal ca1 physiology |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10406435/ https://www.ncbi.nlm.nih.gov/pubmed/37490324 http://dx.doi.org/10.7554/eLife.88206 |
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