An amino acid exchange in the second transmembrane segment of a neuronal nicotinic receptor causes partial epilepsy by altering its desensitization kinetics

Weiland, Sigrid; Witzemann, Veit; Villarroel, Alfredo; Propping, Peter; Steinlein, Ortrud K.

doi:10.1016/s0014-5793(96)01215-x

Cited by 146 publications

(87 citation statements)

References 44 publications

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“…The potential hydrophobic interactions of the F side chain are evident. Our finding that a single F did not promote enhanced desensitization would be consistent with the hypothesis of Weiland et al [16], as a single phenylalanine would not have a companion residue with which to interact hydrophobically. In addition, the fact that we observed the most dramatic effects on desensitization with three or more residues mutated to F is also consistent with this idea, as this would provide additional potential hydrophobic interactions.…”

Section: Discussionsupporting

confidence: 92%

“…When coexpressed with wild type β2 subunits, these mutant receptors display enhanced desensitization [3,16]. This mutation presumably causes epileptic seizures since overall activity of the α4β2 nicotinic receptors would be diminished.…”

Section: Discussionmentioning

confidence: 99%

“…Weiland et al [16] suggested the hydrophobic nature of phenylalanine may be involved in its ability to facilitate desensitization in α4β2 nicotinic receptors. The TM2 6′ residue is exposed to the channel pore in both the closed and open state, although likely more centrally directed in the open state [17].…”

Section: Discussionmentioning

confidence: 99%

“…Of particular relevance to this investigation is the finding that autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is caused by a genetic mutation of the TM2 6′ residue (S → F) in the nicotinic α4 subunit [15]. This mutation results in enhanced desensitization kinetics [3,16].…”

Section: Introductionmentioning

confidence: 99%

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Stoichiometric analysis of the TM2 6′ phenylalanine mutation on desensitization in α1β2 and α1β2γ2 GABAA receptors

Gonzales

Bell-Horner

Dibas

et al. 2008

Neuroscience Letters

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SummaryThe presence of phenylalanine (F) at the 6′ position of transmembrane domain 2 (TM2) in the α4 subunit of α4β2 nicotinic receptors enhances desensitization. As the GABA A receptor affords the ability to study the influence of as few as one and as many as five Fs at this position, we have used it to investigate potential subunit-and stoichiometry-dependent effects of the TM2 6′F mutation on desensitization. Whereas the presence of one F at this position decreased extent of desensitization, desensitization was increased in all configurations that included two or more Fs at the TM2 6′ position; desensitization was particularly rapid with 3 or 4 F residues present. Our results demonstrate the ability of phenylalanine residues at the TM2 6′ position to modulate desensitization is likely conserved in the cys-loop family of ligand-gated ion channels. Moreover, our findings demonstrate both stoichiometric-and subunit-dependent effects of the ability of this mutation to regulate desensitization in GABA A receptors.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Stoichiometric analysis of the TM2 6′ phenylalanine mutation on desensitization in α1β2 and α1β2γ2 GABAA receptors

Gonzales

Bell-Horner

Dibas

et al. 2008

Neuroscience Letters

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“…In this respect, the leucine 247 ␣7 subunit mutant exhibits markedly reduced desensitization (Revah et al, 1991;see above), and is lethal when genetically introduced into mice (Orr-Urtreger et al, 1997). Conversely, a polymorphism (serine to phenylalanine) at position 248 in the pore domain of ␣4 subunits results in faster desensitization of ␣4␤2 nAChRs, but causes a form of human cortical epilepsy (Steinlein et al, 1995;Weiland et al, 1996). While these studies provide some tantalizing evidence that desensitization of nAChRs is a critical feature of CNS functioning, the physiological importance of desensitization is still far from clear.…”

Section: Implications For Desensitization In Physiology and Diseasementioning

confidence: 99%

Desensitization of neuronal nicotinic receptors

2002

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ABSTRACT:The loss of functional response upon continuous or repeated exposure to agonist, desensitization, is an intriguing phenomenon if not as yet a welldefined physiological mechanism. However, detailed evaluation of the properties of desensitization, especially for the superfamily of ligand-gated ion channels, reveals how the nervous system could make important use of this process that goes far beyond simply curtailing excessive receptor stimulation and the prevention of excitotoxicity. Here we will review the mechanistic basis of desensitization and discuss how the subunit-dependent properties and regulation of nicotinic acetylcholine receptor (nAChR) desensitization contribute to the functional diversity of these channels. These studies provide the essential framework for understanding how the physiological regulation of desensitization could be a major determinant of synaptic efficacy by controlling, in both the short and long term, the number of functional receptors. This type of mechanism can be extended to explain how the continuous occupation of desensitized receptors during chronic nicotine exposure contributes to drug addiction, and highlights the potential significance of prolonged nAChR desensitization that would also occur as a result of extended acetylcholine lifetime during treatment of Alzheimer's disease with cholinesterase inhibitors. Thus, a clearer picture of the importance of nAChR desensitization in both normal information processing and in various diseased states is beginning to emerge.

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Possible association of a silent polymorphism in the neuronal nicotinic acetylcholine receptor subunit α4 with common idiopathic generalized epilepsies

et al. 1997

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The alpha4 subunit gene of the neuronal nicotinic acetylcholine receptor (CHRNA4) has recently been identified as the first gene underlying an idiopathic partial epilepsy syndrome in human, autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE). CHRNA4 is located in the candidate region for benign familial neonatal convulsions and low-voltage EEG on chromosome 20q. In the present study, we examined the possible role of CHRNA4 in common subtypes of idiopathic generalized epilepsy (IGE), comprising childhood and juvenile absence epilepsy and juvenile myoclonic epilepsy (JME), by systematically screening the coding region of the gene for sequence variants. We present here a population-based association study testing the hypothesis that variants of the CHRNA4 gene confer genetic susceptibility to common subtypes of IGE. The missense mutation (Ser248Phe), associated with ADNFLE, and four silent polymorphisms in the CHRNA4 gene were genotyped in 103 IGE patients and 92 controls by polymerase chain reaction and subsequent restriction analysis. Without correction for multiple testing, the frequency of the T-allele of the silent CfoI bp595 polymorphism was increased in the entire group of IGE patients (f(T) = 0.085) compared to that in the controls (f(T) = 0.027). The allelic association was not restricted to any subgroup of IGE with either JME or idiopathic absence epilepsies. This result suggests that variation of the CHRNA4 gene, or so-far-undetected sequence variants near the CHRNA4 locus, confer susceptibility to the common IGE syndromes.

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An amino acid exchange in the second transmembrane segment of a neuronal nicotinic receptor causes partial epilepsy by altering its desensitization kinetics

Cited by 146 publications

References 44 publications

Stoichiometric analysis of the TM2 6′ phenylalanine mutation on desensitization in α1β2 and α1β2γ2 GABAA receptors

Stoichiometric analysis of the TM2 6′ phenylalanine mutation on desensitization in α1β2 and α1β2γ2 GABAA receptors

Desensitization of neuronal nicotinic receptors

Possible association of a silent polymorphism in the neuronal nicotinic acetylcholine receptor subunit α4 with common idiopathic generalized epilepsies

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