Pathogenic point mutations in a transmembrane domain of the epsilon subunit increase the Ca2+ permeability of the human endplate ACh receptor.

Pathogenic point mutations in a transmembrane domain of the epsilon subunit increase the Ca2+ permeability of the human endplate ACh receptor. Research Abstract Details 

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Pathogenic point mutations in a transmembrane domain of the epsilon subunit increase the Ca2+ permeability of the human endplate ACh receptor. Abstract Text:

Amalia Di Castro,Katiuscia Martinello,Francesca Grassi,Fabrizio Eusebi,Andrew G Engel,

The epsilon subunit of the human endplate ACh receptor (AChR) is a key determinant of the large fraction of the ACh-evoked current carried by Ca2+ ions (P(f)). Consequently, missense mutations in the epsilon subunit are potential targets for altering the P(f) of human AChR. In this paper we investigate the effects of two pathogenic point mutations in the M2 transmembrane segment AChR epsilon subunit, epsilonT264P and epsilonV259F, that cause slow-channel syndromes (SCS). When expressed in GH4C1 cells, the mutant receptors subunits raise Ca2+ permeability of the receptors approximately 1.5 and approximately 2-fold above that of wild-type, to attain P(f) values of 11.8% (epsilonT264P) and 15.4% (epsilonV259F). The latter value exceeds most P(f) values reported to date for ligand-gated ion channels. Consistent with these findings, the biionic Ca2+ permeability ratio (P(Ca)/P(Cs)) of the mutant AChRs is also increased. Upon repetitive stimulation with ACh, the mutant receptors show an enhanced current run-down compared with wild-type, leading to a strong reduction of their function. We propose that the enhanced Ca2+ permeability of the mutant receptors overrides the protective effect of desensitization and, together with the prolonged opening events of the AChR channel, is an important determinant of the excitotoxic endplate damage in the SCS.

Pathogenic point mutations in a transmembrane domain of the epsilon subunit increase the Ca2+ permeability of the human endplate ACh receptor. Publishing Authors By Initials

A Di Castro,K Martinello,F Grassi,F Eusebi,AG Engel,

For similar proteins: membrane proteins: receptors, cell surface: receptors, neurotransmitter: receptors, cholinergic: receptors, nicotinic research abstracts see: proteins: membrane proteins: receptors, cell surface: receptors, neurotransmitter: receptors, cholinergic: receptors, nicotinic research

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Pathogenic point mutations in a transmembrane domain of the epsilon subunit increase the Ca2+ permeability of the human endplate ACh receptor. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: The Journal of physiology

VOLUME: 579

Page Numbers: 671-7

Journal Abbreviation: J. Physiol. (Lond.)

ISSN: 0022-3751

DAY: 1

MONTH: 02

YEAR: 2007

Pathogenic point mutations in a transmembrane domain of the epsilon subunit increase the Ca2+ permeability of the human endplate ACh receptor. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 266262

Pathogenic point mutations in a transmembrane domain of the epsilon subunit increase the Ca2+ permeability of the human endplate ACh receptor. Keywords Mesh Terms:

KEYWORDS: Receptors, Nicotinic

MESH TERMS: metabolism

Chemical & Substance for Abstract: Pathogenic point mutations in a transmembrane domain of the epsilon subunit increase the Ca2+ permeability of the human endplate ACh receptor. Information

Substance Name: Calcium

Registry Number: 7440-70-2

Grant and Affiliation Information for Pathogenic point mutations in a transmembrane domain of the epsilon subunit increase the Ca2+ permeability of the human endplate ACh receptor.

AFFILIATION: Istituto Pasteur-Fondazione Cenci Bolognetti and Dipartimento di Fisiologia Umana e Farmacologia, Università La Sapienza P.le A. Moro 5; I-00185 Roma, Italy.

Country: England

AGENCY: United States NINDS

GRANT: NS6277

ACRONYM: NS

MEDLINETA: J Physiol

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