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Updated: Oct 10, 2025
Electroconvulsive Seizures in Rats and Fractionation of Their Hippocampi to Examine Seizure-induced Changes in Postsynaptic Density Proteins
Published on: August 15, 2017
14-3-3 proteins stabilize LGI1-ADAM22 levels to regulate seizure thresholds in mice
Norihiko Yokoi1, Yuko Fukata1, Kei Okatsu2
1Division of Membrane Physiology, Department of Molecular and Cellular Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan; Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi 444-8585, Japan.
Understanding protein function in genetic disorders is key. This study reveals that dual phosphorylation of ADAM22 by protein kinase A (PKA) stabilizes LGI1-ADAM22 complexes, preventing epilepsy, with only 10% ADAM22 function needed.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Decreased LGI1-ADAM22 protein complexes are linked to epilepsy and amnesia.
- Regulation of LGI1-ADAM22 levels and the functional threshold for disease prevention remain unclear.
Purpose of the Study:
- To elucidate the regulatory mechanisms of LGI1-ADAM22 complex stability.
- To determine the quantitative functional requirements of LGI1 and ADAM22 in preventing neurological disorders.
Main Methods:
- Genetic and structural analysis of protein interactions.
- Investigated the role of protein kinase A (PKA) and 14-3-3 proteins.
- Utilized hypomorphic mouse models for LGI1 and ADAM22.
Main Results:
- Quantitative dual phosphorylation of ADAM22 by PKA enhances binding to 14-3-3, protecting the complex from degradation.
- PKA activation increases ADAM22 levels.
- Approximately 50% LGI1 and 10% ADAM22 levels suffice to prevent lethal epilepsy.
- ADAM22 function is crucial in both excitatory and inhibitory neurons.
Conclusions:
- ADAM22 phosphorylation by PKA is a key regulator of LGI1-ADAM22 complex stability.
- Therapeutic strategies targeting PKA or 14-3-3 could increase LGI1-ADAM22 complexes for epilepsy treatment.
