2005
DOI: 10.1124/mol.105.011155
|View full text |Cite
|
Sign up to set email alerts
|

Mutations Linked to Autosomal Dominant Nocturnal Frontal Lobe Epilepsy Affect Allosteric Ca2+ Activation of the α4β2 Nicotinic Acetylcholine Receptor

Abstract: Extracellular Ca2ϩ robustly potentiates the acetylcholine response of ␣4␤2 nicotinic receptors. Rat orthologs of five mutations linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)-␣4(S252F), ␣4(S256L), ␣4(ϩL264), ␤2(V262L), and ␤2(V262M)-reduced 2 mM Ca 2ϩ potentiation of the ␣4␤2 1 mM acetylcholine response by 55 to 74%. To determine whether altered allosteric Ca 2ϩ activation or enhanced Ca 2ϩ block caused this reduction, we coexpressed the rat ADNFLE mutations with an ␣4 N-terminal mutatio… Show more

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...
1
1
1
1

Citation Types

3
35
0
1

Year Published

2006
2006
2018
2018

Publication Types

Select...
5
5

Relationship

2
8

Authors

Journals

citations
Cited by 38 publications
(39 citation statements)
references
References 39 publications
3
35
0
1
Order By: Relevance
“…It has been proposed that the decrease in Ca 2ϩ potentiation could contribute to ADNFLE seizures by reducing presynaptic nicotinic receptor activation of inhibitory transmitter release in the cortex or by shifting the balance between nicotinic receptor-induced excitatory and inhibitory transmitter release during bouts of high-frequency cortical synaptic activity in favor of excitatory transmitter release. 215 Whatever the underlying mechanism, the clinical syndrome of ADNFLE is known to respond well to carbamazepine and topiramate. Carbamazepine is a noncompetitive inhibitor of nicotinic receptors that blocks acetylcholine-evoked currents at concentrations in the therapeutic range.…”
Section: Cys-loop Ligand-gated Channelsmentioning
confidence: 99%
“…It has been proposed that the decrease in Ca 2ϩ potentiation could contribute to ADNFLE seizures by reducing presynaptic nicotinic receptor activation of inhibitory transmitter release in the cortex or by shifting the balance between nicotinic receptor-induced excitatory and inhibitory transmitter release during bouts of high-frequency cortical synaptic activity in favor of excitatory transmitter release. 215 Whatever the underlying mechanism, the clinical syndrome of ADNFLE is known to respond well to carbamazepine and topiramate. Carbamazepine is a noncompetitive inhibitor of nicotinic receptors that blocks acetylcholine-evoked currents at concentrations in the therapeutic range.…”
Section: Cys-loop Ligand-gated Channelsmentioning
confidence: 99%
“…Some data show that the mutant receptors have lower EC 50 values than WT receptors (30). Other data show that the mutant receptors are less sensitive than WT receptors to decreased external Ca 2+ (31,32).…”
Section: Another Inadvertent Therapy: Tobacco and Adnflementioning
confidence: 99%
“…One hypothesis suggests that ADNFLE mutations initiate seizures by increasing the sensitivity of ␣4␤2 nicotinic receptors to the endogenous agonist acetylcholine (ACh) (Bertrand et al, 2002). Our own work (Figl et al, 1998;Rodrigues-Pinguet et al, 2003;Rodrigues-Pinguet et al, 2005) and that of others (Steinlein et al, 1997) shows that reduced allosteric Ca 2ϩ potentiation of the ␣4␤2 ACh response is another common feature of ADNFLE mutations.…”
mentioning
confidence: 99%