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4)3(
2)2 Stoichiometry Greatly Exceeds That of (4)2(2)3 Human Acetylcholine ReceptorsDepartmento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain (L.T.); and Department of Neuroscience, University of Pennsylvania Medical School, Philadelphia, Pennsylvania (A.K., J.L.)
Human 
4
2 nicotinic acetylcholine receptors (AChRs) expressed in Xenopus laevis oocytes or transfected cell lines are present as a mixture of two stoichiometries, (4)2(2)3 and (4)3(2)2, which differ depending on whether a 2 or 4 subunit occupies the accessory subunit position corresponding to 1 subunits of muscle AChRs. Pure populations of each stoichiometry can be expressed in oocytes by combining a linked pair of 4 and 2 with free 2 to produce the (4)2(2)3 stoichiometry or with free 4 to produce the (4)3(2)2 stoichiometry. We show that the (4)3(2)2 stoichiometry and the (4)2(2)23 and (4)2(2)25 subtypes in which 3 or 5occupy the accessory positions have much higher permeability to Ca2+ than does (4)2(2)3 and suggest that this could be physiologically significant in triggering signaling cascades if this stoichiometry or these subtypes were found in vivo. We show that Ca2+ permeability is determined by charged amino acids at the extracellular end of the M2 transmembrane domain, which could form a ring of amino acids at the outer end of the cation channel. 4, 5, and 3 subunits all have a homologous glutamate in M2 that contributes to high Ca2+ permeability, whereas 2 has a lysine at this position. Subunit combinations or single amino acids changes at this ring that have all negative charges or a mixture of positive and negative charged amino acids are permeable to Ca2+. All positive charges in the ring prevent Ca2+ permeability. Increasing the proportion of negative charges is associated with increasing permeability to Ca2+.
Address correspondence to: Dr. Jon Lindstrom, Department of Neuroscience, University of Pennsylvania Medical School, 217 Stemmler Hall, 36th and Hamilton Walk, Philadelphia, PA 19104. E-mail: jslkk{at}mail.med.upenn.edu
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