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Neuroscience_topics
Neuroscience: CNS disease, pain, brain research, ion channels, synaptic transmission, channelopathies, neuronal network
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Scooped by Julien Hering, PhD
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Therapeutic potential of NaV1.1 activators

Highlights:- NaV1.1 is the major sodium current in specific inhibitory interneurons.- Interneuronal dysfunction is linked to epilepsies, schizophrenia, and AD.- NaV1.1 plays a modest role in excitatory neurons.- Selective NaV1.1 activators may hold great potential as a novel treatment paradigm.

By Jensen HS et al.,  Trends in Pharmacological Sciences, Volume 35, Issue 3, p113–118, March 2014

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Scooped by Julien Hering, PhD
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Specific deletion of NaV1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome

Heterozygous loss-of-function mutations in the brain sodium channel NaV1.1 cause Dravet syndrome (DS), a pharmacoresistant infantile-onset epilepsy syndrome with comorbidities of cognitive impairment and premature death. Previous studies using a mouse model of DS revealed reduced sodium currents and impaired excitability in GABAergic interneurons in the hippocampus, leading to the hypothesis that impaired excitability of GABAergic inhibitory neurons is the cause of epilepsy and premature death in DS. However, other classes of GABAergic interneurons are less impaired, so the direct cause of hyperexcitability, epilepsy, and premature death has remained unresolved. We generated a floxed Scn1a mouse line and used the Cre-Lox method driven by an enhancer from the Dlx1,2 locus for conditional deletion of Scn1a in forebrain GABAergic neurons. Immunocytochemical studies demonstrated selective loss of NaV1.1 channels in GABAergic interneurons in cerebral cortex and hippocampus. Mice with this deletion died prematurely following generalized tonic-clonic seizures, and they were equally susceptible to thermal induction of seizures as mice with global deletion of Scn1a. Evidently, loss of NaV1.1 channels in forebrain GABAergic neurons is both necessary and sufficient to cause epilepsy and premature death in DS. - by Cheah CD et al.PNAS September 4, 2012 vol. 109 no. 36 14646-14651

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Marked difference in saxitoxin and tetrodoxin affinity for the human nociceptive voltage-gated sodium channel (Nav1.7)

Human nociceptive voltage-gated sodium channel (Nav1.7), a target of significant interest for the development of antinociceptive agents, is blocked by low nanomolar concentrations of (−)-tetrodotoxin(TTX) but not (+)-saxitoxin (STX) and (+)-gonyautoxin-III (GTX-III). These findings question the long-accepted view that the 1.7 isoform is both tetrodotoxin– and saxitoxin-sensitive and identify the outer pore region of the channel as a possible target for the design of Nav1.7-selective inhibitors. Single- and double-point amino acid mutagenesis studies along with whole-cell electrophysiology recordings establish two domain III residues (T1398 and I1399), which occur as methionine and aspartate in other Nav isoforms, as critical determinants of STX and gonyautoxin-III binding affinity. An advanced homology model of the Nav pore region is used to provide a structural rationalization for these surprising results. - by Walker JR et al., PNAS October 30, 2012 vol. 109 no. 44 18102-18107

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