Mutations Linked to Autosomal Dominant Nocturnal Frontal Lobe Epilepsy Affect Allosteric Ca2+ Activation of the α4β2 Nicotinic Acetylcholine Receptor
Abstract
Extracellular Ca(2+) robustly potentiates the acetylcholine response of alpha4beta2 nicotinic receptors. Rat orthologs of five mutations linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)-alpha4(S252F), alpha4(S256L), alpha4(+L264), beta2(V262L), and beta2(V262M)-reduced 2 mM Ca(2+) potentiation of the alpha4beta2 1 mM acetylcholine response by 55 to 74%. To determine whether altered allosteric Ca(2+) activation or enhanced Ca(2+) block caused this reduction, we coexpressed the rat ADNFLE mutations with an alpha4 N-terminal mutation, alpha4(E180Q), that abolished alpha4beta2 allosteric Ca(2+) activation. In each case, Ca(2+) inhibition of the double mutants was less than that expected from a Ca(2+) blocking mechanism. In fact, the effects of Ca(2+) on the ADNFLE mutations near the intracellular end of the M2 region-alpha4(S252F) and alpha4(S256L)-were consistent with a straightforward allosteric mechanism. In contrast, the effects of Ca(2+) on the ADNFLE mutations near the extracellular end of the M2 region-alpha4(+L264)beta2, beta2(V262L), and beta2(V262M)-were consistent with a mixed mechanism involving both altered allosteric activation and enhanced block. However, the effects of 2 mM Ca(2+) on the alpha4beta2, alpha4(+L264)beta2, and alpha4beta2(V262L) single-channel conductances, the effects of membrane potential on the beta2(V262L)-mediated reduction in Ca(2+) potentiation, and the effects of eliminating the negative charges in the extracellular ring on this reduction failed to provide any direct evidence of mutant-enhanced Ca(2+) block. Moreover, analyses of the alpha4beta2, alpha4(S256L), and alpha4(+L264) Ca(2+) concentration-potentiation relations suggested that the ADNFLE mutations reduce Ca(2+) potentiation of the alpha4beta2 acetylcholine response by altering allosteric activation rather than by enhancing block.
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Other data show that ADNFLE mutant receptors are less sensitive than WT receptors to decreased external Ca2+.
“Other data show that the mutant receptors are less sensitive than WT receptors to decreased external Ca2+ (31,32).”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [31]
Heterologous expression shows that ADNFLE receptors have a gain of function.
“In experiments conducted since ADNFLE was mapped in 1995, heterologous expression shows that ADNFLE receptors have a gain of function.”
From Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery (2009) · cites this paper as [31]
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- Authors
- Rodrigues-Pinguet, N. O., Pinguet, T. J., Figl, A., Lester, H. A., & Cohen, B. N.
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2005-08
- Volume
- 68
- Issue
- 2
- Pages
- 487-501
- ISSN
- 0026-895X (ISSN-L)
- OpenAlex
- W2152143103
- Cited by
- 42
- References
- 41
- Citations by year
- 2025: 2 · 2024: 2 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 1 · 2016: 1 · 2015: 2 · 2012: 3
- FWCI
- 1.75
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS0438000-04S1, NS011756, NS0438000, R01NS011756)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- autosomal dominant nocturnal frontal lobe epilepsy, nicotinic acetylcholine receptors, alpha4beta2 nicotinic receptor, calcium block, receptor mutations, alpha4 subunit, beta2 subunit, single-channel conductance, membrane potential, rat model
- MeSH terms
- Allosteric Regulation, Amino Acid Sequence, Animals, Calcium, Dose-Response Relationship, Drug, Female, Molecular Sequence Data, Mutation, Receptors, Nicotinic, Xenopus laevis, Epilepsy, Frontal Lobe, Rats
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