Linked Life Data

20962009

Source:http://linkedlifedata.com/resource/pubmed/id/20962009

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
Pt 23
pubmed:dateCreated
2010-12-3
pubmed:abstractText
The spectrin cytoskeleton has an important function in the targeting of proteins to excitable membrane domains. In axons, ?IV-spectrin stabilizes voltage-gated sodium (Nav) channel clusters at nodes of Ranvier and axon initial segments, two regions crucial for the generation and conduction of action potentials. Here, I investigated the physiology of the neuromuscular junction and peripheral nerves in quivering-3J mice, which show a frame-shift base insertion in the Spnb4 gene and lack the C-terminus of ?IV-spectrin. The quivering-3J mice show prominent spontaneous and evoked hyperactivities at diaphragm neuromuscular junctions. These neuromyotonic and myokymic discharges were more prominent in adult animals when tremors and ataxia were pronounced. Recordings of sciatic and phrenic nerves showed that the hyperactivities originate in myelinated axons distally from nerve terminals. Axon and myelin structure in the PNS were unaffected in quivering-3J mice. Of interest, KCNQ2 subunit aggregates were undetectable at PNS and CNS nodes, whereas Nav and Kv1.1/Kv1.2 channels were properly concentrated at nodal and juxtaparanodal regions, respectively. The protein level of KCNQ2 subunits was normal in mutant animals, suggesting that KCNQ2 subunit absence stems from clustering or trafficking defects in axons. The quivering-3J nodes also presented high densities of ankyrin-G and CK2?, two cytosolic molecules involved with aggregating Nav and KCNQ2/3 channels in axons. Because ?IV-spectrin does not interact with KCNQ2/3 subunits, it is suspected that ?IV-spectrin regulates the distribution of KCNQ2/3 subunits in axonal subdomains via regulatory partners. Retigabine, an activator of KCNQ2/3 channels, attenuated the repetitive activities in quivering-3J mice, suggesting that depletion of KCNQ2 subunits at nodes initiates neuromyotonic/myokymic discharges. These findings demonstrate that spectrin cytoskeleton finely regulates ion channel distribution and implicates KCNQ2/3 subunits in axonal excitability and in myokymia aetiology.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
1469-7793
pubmed:author
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
588
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4719-30
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
The C-terminal domain of ßIV-spectrin is crucial for KCNQ2 aggregation and excitability at nodes of Ranvier.
pubmed:affiliation
Département Signalisation Neuronale, CRN2M, UMR 6231, CNRS, Faculté de Médecine - Secteur Nord, Université de la Méditerranée-Université Paul Cézanne, CS80011, Bd Pierre Dramard, 13344 Marseille Cedex 15, France. jerome.devaux@univmed.fr
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural