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Nicotinic acetylcholine receptors (nAChRs) are cation-selective ligand-gated ion channels exhibiting variable Ca 2+  permeability depending on their subunit composition. The Ca 2+  permeability is a crucial functional parameter to understand the physiological role of nAChRs, in particular considering their ability to modulate Ca 2+ -dependent processes such as neurotransmitter release. The rings of extracellular and intracellular charged amino acid residues adjacent to the pore-lining TM2 transmembrane segment have been shown to play a key role in the cation selectivity of these receptor channels, but to date a quantitative relationship between these structural determinants and the Ca 2+  permeability of nAChRs is lacking. In the last years the Ca 2+  permeability of several nAChR subtypes has been experimentally evaluated, in terms of fractional Ca 2+  current ( Pf , i.e., the percentage of the total current carried by Ca 2+  ions). In the present study, the available  Pf -values of nAChRs are used to build a simplified modular model describing the contribution of the charged residues in defined regions flanking TM2 to the selectivity filter controlling Ca 2+  influx. This model allows to predict the currently unknown  Pf -values of existing nAChRs, as well as the hypothetical Ca 2+  permeability of subunit combinations not able to assemble into functional receptors. In particular, basing on the amino acid sequences, a  Pf  > 50% would be associated with homomeric nAChRs composed by different α subunits, excluding α7, α9, and α10. Furthermore, according to the model, human α7β2 receptors should have  Pf -values ranging from 3.6% (4:1 ratio) to 0.1% (1:4 ratio), much lower than the 11.4% of homomeric α7 nAChR. These results help to understand the evolution and the function of the large diversity of the nicotinic receptor family.

The Distribution of Charged Amino Acid Residues and the Ca2+ Permeability of Nicotinic Acetylcholine Receptors: A Predictive Model