Nedd4-2 haploinsufficiency causes hyperactivity and increased sensitivity to inflammatory stimuli.
Nedd4-2 (NEDD4L in humans) is a ubiquitin protein ligase best known for its role in regulating ion channel internalization and turnover. Nedd4-2 deletion in mice causes perinatal lethality associated with increased epithelial sodium channel (ENaC) expression in lung and kidney. Abundant data suggest that Nedd4-2 plays a role in neuronal functions and may be linked to epilepsy and dyslexia in humans. We used a mouse model of Nedd4-2 haploinsufficiency to investigate whether an alteration in Nedd4-2 levels of expression affects general nervous system functions. We found that Nedd4-2 heterozygous mice are hyperactive, have increased basal synaptic transmission and have enhanced sensitivity to inflammatory pain. Thus, Nedd4-2 heterozygous mice provide a new genetic model to study inflammatory pain. These data also suggest that in human, SNPs affecting NEDD4L levels may be involved in the development of neuropsychological deficits and peripheral neuropathies and may help unveil the genetic basis of comorbidities.
Neural Development Section, Mouse Cancer Genetics Program, CCR, NCI, Frederick, MD, 21702, USA.
Sudhirkumar
S
Yanpallewar
Neural Development Section, Mouse Cancer Genetics Program, CCR, NCI, Frederick, MD, 21702, USA.
Ting
T
Wang
Neural Development Section, Mouse Cancer Genetics Program, CCR, NCI, Frederick, MD, 21702, USA.
Dawn C I
DC
Koh
Neural Development Section, Mouse Cancer Genetics Program, CCR, NCI, Frederick, MD, 21702, USA.|Physiological Science Section, Department of Experimental and Clinical Medicine, University of Florence, Italy.
Eros
E
Quarta
Neural Development Section, Mouse Cancer Genetics Program, CCR, NCI, Frederick, MD, 21702, USA.|Department of Molecular and Clinical Sciences, Marche Polytechnic University, Ancona, Italy.
Gianluca
G
Fulgenzi
Neural Development Section, Mouse Cancer Genetics Program, CCR, NCI, Frederick, MD, 21702, USA.
Lino
L
Tessarollo
D000818:Animals; D056547:CA1 Region, Hippocampal / Q000201:enzymology / Q000503:physiopathology; D004195:Disease Models, Animal; D004827:Epilepsy / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D019706:Excitatory Postsynaptic Potentials; D057895:Haploinsufficiency; D006579:Heterozygote; D006801:Humans; D006948:Hyperkinesis / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D017774:Long-Term Potentiation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000075702:Nedd4 Ubiquitin Protein Ligases / Q000172:deficiency* / Q000235:genetics*; D010146:Pain / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D009435:Synaptic Transmission
D000075702:Nedd4 Ubiquitin Protein Ligases; C000618485:Nedd4L protein, human; C000618461:Nedd4l protein, mouse