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First published online on May 16, 2003.
 Copyright © 2003 by The Physiological Society
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Received February 10, 2003
Accepted after revision April 15, 2003

Five ADNFLE mutations reduce the Ca2+ dependence of the {alpha}4{beta}2 acetylcholine response

Nivalda Rodrigues-Pinguet1, Li Jia2, Maureen Li3, Antonio Figl3, Alwin Klaassen4, Anthony Truong3, Henry A. Lester5, and B. N. Cohen6*

1 Division of Biomedical Sciences, University of California, Riverside, CA 92521-0121 and Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA
2 Computer Science Department, University of California, Riverside, CA 92521-0121, USA
3 Division of Biomedical Sciences, University of California, Riverside, CA 92521-0121, USA
4 Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095-1759, USA
5 Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA
6 Division of Biology 156-29, California Institute of Technology, Pasadena, CA 91125, USA

* To whom correspondence should be addressed. E-mail: bncohen{at}caltech.edu.

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 ({alpha}4 or {beta}2), 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 {alpha}4{beta}2 nAChR. Ca2+ modulation may prevent presynaptic {alpha}4{beta}2 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 {alpha}4{beta}2-mediated glutamate release during such bouts.




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