In:
The Journal of Neuroscience, Society for Neuroscience, Vol. 33, No. 42 ( 2013-10-16), p. 16586-16593
Abstract:
Voltage-gated potassium channel Kv10.2 ( KCNH5 ) is expressed in the nervous system, but its functions and involvement in human disease are poorly understood. We studied a human Kv10.2 channel mutation (R327H) recently identified in a child with epileptic encephalopathy and autistic features. Using multistate structural modeling, we demonstrate that the Arg327 residue in the S4 helix of voltage-sensing domain has strong ionic interactions with negatively charged residues within the S1–S3 helices in the resting (closed) and early-activation state but not in the late-activation and fully-activated (open) state. The R327H mutation weakens ionic interactions between residue 327 and these negatively charged residues, thus favoring channel opening. Voltage-clamp analysis showed a strong hyperpolarizing (∼70 mV) shift of voltage dependence of activation and an acceleration of activation. Our results demonstrate the critical role of the Arg327 residue in stabilizing the channel closed state and explicate for the first time the structural and functional change of a Kv10.2 channel mutation associated with neurological disease.
Type of Medium:
Online Resource
ISSN:
0270-6474
,
1529-2401
DOI:
10.1523/JNEUROSCI.2307-13.2013
Language:
English
Publisher:
Society for Neuroscience
Publication Date:
2013
detail.hit.zdb_id:
1475274-8
SSG:
12