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Volume 17, Number 23,
Issue of December 1, 1997
pp. 9035-9047
Mutation Causing Autosomal Dominant Nocturnal Frontal Lobe
Epilepsy Alters Ca2+ Permeability, Conductance, and Gating
of Human  4 2 Nicotinic Acetylcholine Receptors
Received July 7, 1997; revised Sept. 17, 1997; accepted Sept. 18, 1997.
Alexander Kuryatov,
Volodymyr Gerzanich,
Mark Nelson,
Felix Olale, and
Jon Lindstrom
Department of Neuroscience, Medical School, University of
Pennsylvania, Philadelphia, Pennsylvania 19104-6074
A mutation (S247F) in the channel-lining domain (M2) of the  4
nicotinic acetylcholine receptor (AChR) subunit has previously been
linked genetically to autosomal dominant nocturnal frontal lobe
epilepsy (ADNFLE).
To better understand the functional significance of this mutation, we
characterized the properties of mutant and wild-type human 4 2
AChRs expressed in Xenopus oocytes. Both had similar expression levels and EC50 values for ACh and nicotine.
Substantial use-dependent functional upregulation was found for mutant
42 AChRs, but not for wild type. Mutant AChR responses showed
faster desensitization, slower recovery from desensitization, less
inward rectification, and virtually no Ca2+
permeability as compared with wild-type 42 AChRs. Addition of the
5 subunit restored Ca2+ permeability to the
mutant 425 AChRs. At  80 mV, wild-type 42 AChR single
channel currents exhibited two conductances, each with two mean open
times ( 1 = 17 pS,  1 = 3.7 msec, and 2 = 23.4 msec; 2 = 28 pS,
1 = 1.9 msec, and 2 = 8.1 msec). In
contrast, mutant AChRs exhibited only one conductance of 11 pS, with
1 = 1.9 msec and 2 = 4.1 msec.
The net effect of the mutation is to reduce AChR function. This could
result in the hyperexcitability characteristic of epilepsy if the
mutant AChRs were part of an inhibitory circuit, e.g., presynaptically
regulating the release of GABA. In the minority of AChRs containing the
5 subunit, the overall functionality of these AChRs could be
maintained despite the mutation in the 4 subunit.
Key words:
autosomal dominant nocturnal frontal lobe epilepsy;
nicotinic acetylcholine receptors;
calcium permeability;
desensitization;
epilepsy;
single channel
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|
|
|
|
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|
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|
|
|
|
|
|
|
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21(17):
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|
|
|
|
|
|
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April 1, 2001;
16(4):
271 - 280.
[Abstract]
[PDF]
|
|
|
|
|
|
|
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March 15, 2001;
21(6):
1819 - 1829.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. G. Wilson and A. Karlin
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PNAS,
January 10, 2001;
(2001)
31567798.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
A. Gambardella, G. Annesi, M. De Fusco, A. Patrignani, U. Aguglia, F. Annesi, A. A. Pasqua, P. Spadafora, R. L. Oliveri, P. Valentino, et al.
A new locus for autosomal dominant nocturnal frontal lobe epilepsy maps to chromosome 1
Neurology,
November 28, 2000;
55(10):
1467 - 1471.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Alkondon, E. F. R. Pereira, H. M. Eisenberg, and E. X. Albuquerque
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J. Neurosci.,
January 1, 2000;
20(1):
66 - 75.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Hirose, H. Iwata, H. Akiyoshi, K. Kobayashi, M. Ito, K. Wada, S. Kaneko, and A. Mitsudome
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Neurology,
November 1, 1999;
53(8):
1749 - 1749.
[Abstract]
[Full Text]
[PDF]
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R. Zwart and H. P. M. Vijverberg
Four Pharmacologically Distinct Subtypes of alpha 4beta 2 Nicotinic Acetylcholine Receptor Expressed in Xenopus laevis Oocytes
Mol. Pharmacol.,
December 1, 1998;
54(6):
1124 - 1131.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
G. G. Wilson and A. Karlin
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PNAS,
January 30, 2001;
98(3):
1241 - 1248.
[Abstract]
[Full Text]
[PDF]
|
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|
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