Nedd4-2 haploinsufficiency in mice causes increased seizure susceptibility and impaired Kir4.1 ubiquitination. 2021

Xiaoliang Liu, and Hebo Zhang, and Bijun Zhang, and Jianqiao Tu, and Xiaoming Li, and Yanyan Zhao
Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang, China.

Neural precursor cell expressed developmentally down-regulated gene 4-like (NEDD4-2) encodes a ubiquitin E3 ligase that is involved in epileptogenesis with mechanisms needing further investigation. We constructed a novel Nedd4-2+/- mouse model with half level of both Nedd4-2 long and short isoforms in the brain. Nedd4-2 haploinsufficiency caused increased susceptibility and severity of pentylenetetrazole (PTZ)-induced seizures. Of the 3379 proteins identified by the hippocampal proteomic analysis, 55 were considered altered in Nedd4-2+/- mice compared with wild-type control, among which the inwardly rectifying K+ channel Kir4.1 was up-regulated by 1.83-fold. Kir4.1 was subsequently confirmed to be less ubiquitinated in response to comprised Nedd4-2 in mouse brains and C6 cells. Kir4.1 associated with Nedd4-2 through the threonine312-proline motif in the intracellular domain by target mutagenesis. Adaptor protein 14-3-3 facilitated Nedd4-2-mediated ubiquitination of Kir4.1. Our data consolidate the detailed molecular mechanism of Nedd4-2-mediated Kir4.1 ubiquitination, and provide a possible relationship between increased seizure susceptibility and impaired Kir4.1 ubiquitination in the brain.

UI MeSH Term Description Entries
D008297 Male Males
D008810 Mice, Inbred C57BL One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases. Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D010433 Pentylenetetrazole A pharmaceutical agent that displays activity as a central nervous system and respiratory stimulant. It is considered a non-competitive GAMMA-AMINOBUTYRIC ACID antagonist. Pentylenetetrazole has been used experimentally to study seizure phenomenon and to identify pharmaceuticals that may control seizure susceptibility. Leptazole,Pentamethylenetetrazole,Pentetrazole,Cardiazol,Corasol,Corazol,Corazole,Korazol,Korazole,Metrazol,Metrazole,Pentazol,Pentylenetetrazol
D003292 Convulsants Substances that act in the brain stem or spinal cord to produce tonic or clonic convulsions, often by removing normal inhibitory tone. They were formerly used to stimulate respiration or as antidotes to barbiturate overdose. They are now most commonly used as experimental tools. Convulsant,Convulsant Effect,Convulsant Effects,Effect, Convulsant,Effects, Convulsant
D000075702 Nedd4 Ubiquitin Protein Ligases E3 ubiquitin ligases that consist of four WW DOMAINS. They accept UBIQUITIN from E2 UBIQUITIN-CONJUGATING ENZYME as a thioester via their C-terminal HECT domains and transfer it specifically to the 63rd LYSINE residue (Lys-63) of target proteins. NEDD4 targets include many proteins and receptors with important functions for cell growth and homeostasis such as VEGFR-2; FGFR1 TYROSINE KINASE; and ERBB-4 RECEPTOR. They play a critical role in the internalization of these receptors, their degradation by LYSOSOMES, and also function as part of the ESCRT complex in VIRUS RELEASE. Nedd4 Proteins,Neuronal Precursor Cell-Expressed Developmentally Down-Regulated 4 Ligase,Neuronal Precursor Cell Expressed Developmentally Down Regulated 4 Ligase
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D012640 Seizures Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder." Absence Seizure,Absence Seizures,Atonic Absence Seizure,Atonic Seizure,Clonic Seizure,Complex Partial Seizure,Convulsion,Convulsions,Convulsive Seizure,Convulsive Seizures,Epileptic Seizure,Epileptic Seizures,Generalized Absence Seizure,Generalized Tonic-Clonic Seizures,Jacksonian Seizure,Myoclonic Seizure,Non-Epileptic Seizure,Nonepileptic Seizure,Partial Seizure,Seizure,Seizures, Convulsive,Seizures, Focal,Seizures, Generalized,Seizures, Motor,Seizures, Sensory,Tonic Clonic Seizure,Tonic Seizure,Tonic-Clonic Seizure,Atonic Absence Seizures,Atonic Seizures,Clonic Seizures,Complex Partial Seizures,Convulsion, Non-Epileptic,Generalized Absence Seizures,Myoclonic Seizures,Non-Epileptic Seizures,Nonepileptic Seizures,Partial Seizures,Petit Mal Convulsion,Seizures, Auditory,Seizures, Clonic,Seizures, Epileptic,Seizures, Gustatory,Seizures, Olfactory,Seizures, Somatosensory,Seizures, Tonic,Seizures, Tonic-Clonic,Seizures, Vertiginous,Seizures, Vestibular,Seizures, Visual,Single Seizure,Tonic Seizures,Tonic-Clonic Seizures,Absence Seizure, Atonic,Absence Seizure, Generalized,Absence Seizures, Atonic,Absence Seizures, Generalized,Auditory Seizure,Auditory Seizures,Clonic Seizure, Tonic,Clonic Seizures, Tonic,Convulsion, Non Epileptic,Convulsion, Petit Mal,Convulsions, Non-Epileptic,Focal Seizure,Focal Seizures,Generalized Seizure,Generalized Seizures,Generalized Tonic Clonic Seizures,Generalized Tonic-Clonic Seizure,Gustatory Seizure,Gustatory Seizures,Motor Seizure,Motor Seizures,Non Epileptic Seizure,Non Epileptic Seizures,Non-Epileptic Convulsion,Non-Epileptic Convulsions,Olfactory Seizure,Olfactory Seizures,Partial Seizure, Complex,Partial Seizures, Complex,Seizure, Absence,Seizure, Atonic,Seizure, Atonic Absence,Seizure, Auditory,Seizure, Clonic,Seizure, Complex Partial,Seizure, Convulsive,Seizure, Epileptic,Seizure, Focal,Seizure, Generalized,Seizure, Generalized Absence,Seizure, Generalized Tonic-Clonic,Seizure, Gustatory,Seizure, Jacksonian,Seizure, Motor,Seizure, Myoclonic,Seizure, Non-Epileptic,Seizure, Nonepileptic,Seizure, Olfactory,Seizure, Partial,Seizure, Sensory,Seizure, Single,Seizure, Somatosensory,Seizure, Tonic,Seizure, Tonic Clonic,Seizure, Tonic-Clonic,Seizure, Vertiginous,Seizure, Vestibular,Seizure, Visual,Seizures, Generalized Tonic-Clonic,Seizures, Nonepileptic,Sensory Seizure,Sensory Seizures,Single Seizures,Somatosensory Seizure,Somatosensory Seizures,Tonic Clonic Seizures,Tonic-Clonic Seizure, Generalized,Tonic-Clonic Seizures, Generalized,Vertiginous Seizure,Vertiginous Seizures,Vestibular Seizure,Vestibular Seizures,Visual Seizure,Visual Seizures
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D054875 Ubiquitination The act of ligating UBIQUITINS to PROTEINS to form ubiquitin-protein ligase complexes to label proteins for transport to the PROTEASOME ENDOPEPTIDASE COMPLEX where proteolysis occurs. Ubiquitylation
D056827 Endosomal Sorting Complexes Required for Transport A set of protein subcomplexes involved in PROTEIN SORTING of UBIQUITINATED PROTEINS into intraluminal vesicles of MULTIVESICULAR BODIES and in membrane scission during formation of intraluminal vesicles, during the final step of CYTOKINESIS, and during the budding of enveloped viruses. The ESCRT machinery is comprised of the protein products of Class E vacuolar protein sorting genes. ESCRT Complexes,ESCRT I,ESCRT II,ESCRT III,ESCRT Machinery,Endosomal Sorting Complex Required for Transport,Endosomal Sorting Complex Required for Transport I,Endosomal Sorting Complex Required for Transport II,Endosomal Sorting Complex Required for Transport III,Endosomal Sorting Complex Required for Transport Machinery,Complexes, ESCRT,Machinery, ESCRT

Related Publications

Xiaoliang Liu, and Hebo Zhang, and Bijun Zhang, and Jianqiao Tu, and Xiaoming Li, and Yanyan Zhao
September 2016, Scientific reports,
Xiaoliang Liu, and Hebo Zhang, and Bijun Zhang, and Jianqiao Tu, and Xiaoming Li, and Yanyan Zhao
October 2018, American journal of physiology. Renal physiology,
Xiaoliang Liu, and Hebo Zhang, and Bijun Zhang, and Jianqiao Tu, and Xiaoming Li, and Yanyan Zhao
March 2008, Free radical biology & medicine,
Xiaoliang Liu, and Hebo Zhang, and Bijun Zhang, and Jianqiao Tu, and Xiaoming Li, and Yanyan Zhao
March 2009, Human molecular genetics,
Xiaoliang Liu, and Hebo Zhang, and Bijun Zhang, and Jianqiao Tu, and Xiaoming Li, and Yanyan Zhao
February 2017, PLoS genetics,
Xiaoliang Liu, and Hebo Zhang, and Bijun Zhang, and Jianqiao Tu, and Xiaoming Li, and Yanyan Zhao
March 2004, Free radical biology & medicine,
Xiaoliang Liu, and Hebo Zhang, and Bijun Zhang, and Jianqiao Tu, and Xiaoming Li, and Yanyan Zhao
May 2001, Nature genetics,
Xiaoliang Liu, and Hebo Zhang, and Bijun Zhang, and Jianqiao Tu, and Xiaoming Li, and Yanyan Zhao
August 2005, Cancer research,
Xiaoliang Liu, and Hebo Zhang, and Bijun Zhang, and Jianqiao Tu, and Xiaoming Li, and Yanyan Zhao
March 2016, Molecular brain,
Xiaoliang Liu, and Hebo Zhang, and Bijun Zhang, and Jianqiao Tu, and Xiaoming Li, and Yanyan Zhao
January 2024, The Journal of cell biology,
Copied contents to your clipboard!