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Five ADNFLE Mutations Reduce the Ca²⁺ Dependence of the Mammalian α4β2 Acetylcholine Response

Rodrigues-Pinguet, Nivalda and Jia, Li and Li, Maureen and Figl, Antonio and Klaassen, Alwin and Truong, Anthony and Lester, Henry A. and Cohen, Bruce N. (2003) Five ADNFLE Mutations Reduce the Ca²⁺ Dependence of the Mammalian α4β2 Acetylcholine Response. Journal of Physiology, 550 (1). pp. 11-26. ISSN 0022-3751. PMCID PMC2343021. https://resolver.caltech.edu/CaltechAUTHORS:20200428-095147285

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Abstract

Five nicotinic acetylcholine receptor (nAChR) mutations are currently linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). The similarity of their clinical symptoms suggests that a common functional anomaly of the mutations underlies ADNFLE seizures. To identify this anomaly, we constructed rat orthologues (S252F, +L264, S256L, V262L, V262M) of the human ADNFLE mutations, expressed them in Xenopus oocytes with the appropriate wild‐type (WT) subunit (α4 or β2), and studied the Ca²⁺ dependence of their ACh responses. All the mutations significantly reduced 2 mM Ca²⁺‐induced increases in the 30 μM ACh response (P < 0.05). Consistent with a dominant mode of inheritance, this reduction persisted in oocytes injected with a 1:1 mixture of mutant and WT cRNA. BAPTA injections showed that the reduction was not due to a decrease in the secondary activation of Ca²⁺‐activated Cl⁻ currents. The S256L mutation also abolished 2 mM Ba²⁺ potentiation of the ACh response. The S256L, V262L and V262M mutations had complex effects on the ACh concentration‐response relationship but all three mutations shifted the concentration‐response relationship to the left at [ACh]⩾ 30 μM. Co‐expression of the V262M mutation with a mutation (E180Q) that abolished Ca²⁺ potentiation resulted in 2 mM Ca²⁺ block, rather than potentiation, of the 30 μM ACh response, suggesting that the ADNFLE mutations reduce Ca²⁺ potentiation by enhancing Ca²⁺ block of the α4β2 nAChR. Ca²⁺ modulation may prevent presynaptic α4β2 nAChRs from overstimulating glutamate release at central excitatory synapses during bouts of synchronous, repetitive activity. Reducing the Ca²⁺ dependence of the ACh response could trigger seizures by increasing α4β2‐mediated glutamate release during such bouts.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1113/jphysiol.2003.036681DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc2343021/PubMed CentralArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2003 The Physiological Society. Received 10 February 2003; accepted after revision 15 April 2003; first published online 16 May 2003) This research was supported by the California Tobacco‐Related Disease Research Program (6KT‐0208), the Epilepsy Foundation (EFA/COHEN‐01) and the NIH (NS43800, NS11756). We thank Kira Kostenka for help with the oocytes and Cesar Labarca, Purnima Deshpande, Carlos Fonck, Raad Nashmi, Andrew Tapper, Johannes Schwarz and Jim Boulter for comments.
Funders:
Funding AgencyGrant Number
California Tobacco-Related Disease Research Program6KT‐0208
Epilepsy Foundation of AmericaEFA/COHEN‐01
NIHNS43800
NIHNS11756
Issue or Number:1
PubMed Central ID:PMC2343021
Record Number:CaltechAUTHORS:20200428-095147285
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200428-095147285
Official Citation:Rodrigues‐Pinguet, N., Jia, L., Li, M., Figl, A., Klaassen, A., Truong, A., Lester, H.A. and Cohen, B.N. (2003), Five ADNFLE Mutations Reduce the Ca2+ Dependence of the Mammalian α4β2 Acetylcholine Response. The Journal of Physiology, 550: 11-26. doi:10.1113/jphysiol.2003.036681
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:102869
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:28 Apr 2020 17:16
Last Modified:24 Nov 2020 18:01

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