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Received for publication September 7, 2006.
Revised November 21, 2006.
Accepted for publication November 28, 2006.
4)3(
2)2 Stoichiometry Greatly Exceeds That of (4)2(2)3 Human AChRs
Human 
4
2 nicotinic acetylcholine receptors (AChRs) expressed in Xenopus 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 5 occupy the accessory positions have much higher permeability to Ca++ 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 Ca++ 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 which contributes to high Ca++ permeability, whereas 2 has a lysine at this position. Subunit combinations or single amino acids changes at this ring which have all negative charges or a mixture of positive and negative charged amino acids are permeable to Ca++. All positive charges in the ring prevent Ca++ permeability. Increasing the proportion of negative charges is associated with increasing permeability to Ca++.
Key words:
Nicotinic cholinergic, Func. analysis receptor/ion channel mutants
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