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J Physiol Volume 579, Number 3, 671-677, March 15, 2007 DOI: 10.1113/jphysiol.2007.127977
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RAPID REPORT

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

 Amalia Di Castro1, Katiuscia Martinello1, Francesca Grassi1, Fabrizio Eusebi1,2,3 and Andrew G. Engel4

1 Istituto Pasteur-Fondazione Cenci Bolognetti and Dipartimento di Fisiologia Umana e Farmacologia, Università ‘La Sapienza’ P.le A. Moro 5; I-00185 Roma, Italy
2 Neuromed, Istituto di Ricovero e Cura a Carattere Scientifico, Via Atinese 18; I-86077 Pozzilli, Italy
3 Istituto di Medicina e Scienza dello Sport, CONI Servizi, Roma, Italy
4 Muscle Research Laboratory, Mayo Clinic, Rochester, MN 55905, USA

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 (Pf). Consequently, missense mutations in the {epsilon} subunit are potential targets for altering the Pf of human AChR. In this paper we investigate the effects of two pathogenic point mutations in the M2 transmembrane segment AChR {epsilon} subunit, {epsilon}T264P and {epsilon}V259F, that cause slow-channel syndromes (SCS). When expressed in GH4C1 cells, the mutant receptors subunits raise Ca2+ permeability of the receptors ~1.5 and ~2-fold above that of wild-type, to attain Pf values of 11.8% ({epsilon}T264P) and 15.4% ({epsilon}V259F). The latter value exceeds most Pf values reported to date for ligand-gated ion channels. Consistent with these findings, the biionic Ca2+ permeability ratio (PCa/PCs) 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.

(Received 11 January 2007; accepted after revision 31 January 2007; first published online 1 February 2007)
Corresponding author Correspondence: F. Grassi. Dipartimento di Fisiologia Umana e Farmacologia, Università ‘La Sapienza’ P.le A. Moro 5; I-00185 Roma, Italy. Email: francesca.grassi{at}uniroma1.it






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