Activation of SGK1.1 up-regulates the M-current in the presence of epilepsy mutations
Martin-Batista, E.; Manville, R. W.; Rivero-Perez, B.; Bartolome-Martin, D.; Alvarez de la Rosa, D.; Abbott, G. W.; Giraldez, T.
Show abstract
In the central nervous system, the M-current plays a critical role in regulating subthreshold electrical excitability of neurons, determining their firing properties and responsiveness to synaptic input. The M-channel is mainly formed by subunits Kv7.2 and Kv7.3 that co-assemble to form a heterotetrametric channel. Mutations in Kv7.2 and Kv7.3 are associated with hyperexcitability phenotypes including benign familial neonatal epilepsy (BFNE) and neonatal epileptic encephalopathy (NEE). SGK1.1, the neuronal isoform of the serum and glucocorticoids-regulated kinase 1 (SGK1), increases M-current density in neurons, leading to reduced excitability and protection against seizures. Herein, using two-electrode voltage clamp on Xenopus laevis oocytes, we demonstrate that SGK1.1 selectively activates heteromeric Kv7 subunit combinations underlying the M-current. Importantly, activated SGK1.1 is able to up-regulate M-channel activity in the presence of two different epilepsy mutations found in Kv7.2 subunit, R207W and A306T. In addition, proximity ligation assays in the N2a cell line allowed us to address the effect of these mutations on Kv7-SGK1.1-Nedd4 molecular associations, a proposed pathway underlying M-channel up-regulation by SGK1.1
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- BK channel properties correlate with neurobehavioral severity in three KCNMA1-linked channelopathy mouse models 96%
- Kv2.1 mediates spatial and functional coupling of L-type calcium channels and ryanodine receptors in neurons 95%
- Seizures, behavioral deficits and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy 94%
Similar papers in this journal
- Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABAA receptors 95%
- Epilepsy and neurobehavioral abnormalities in mice with a KCNB1 pathogenic variant that alters conducting and non-conducting functions of KV2.1 95%
- Kcns3 Deficiency Disrupts Parvalbumin Neuron Physiology in Mouse Prefrontal Cortex: Implications for the pathophysiology of schizophrenia 95%
Similar papers in this journal
Similar papers in this journal
- Parkinson's Disease-Linked Kir4.2 Mutation R28C Leads to Loss of Ion Channel Function 96%
- Cation-chloride cotransporters and the polarity of GABA signaling in mouse hippocampal parvalbumin interneurons 94%
- A novel ion conducting route besides the central pore in an inherited mutant of G-protein-gated inwardly rectifying K+ channel 94%
Similar papers in this journal
- Functional crosstalk between phosphorylation and disease-causing mutations in the cardiac sodium channel Nav1.5 93%
- Dissociation of SYNGAP1 Enzymatic and Structural Roles: Intrinsic Excitability and Seizure Susceptibility 93%
- Altered integration of excitatory inputs onto the basal dendrites of layer 5 pyramidal neurons in a mouse model of Fragile X Syndrome 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.