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Physostigmine can potentiate and inhibit neuronal nicotinic receptors, in addition to inhibiting the activity of acetylcholinesterase. We found that receptors containing three copies of the α 2 subunit are inhibited by low concentrations of physostigmine in contrast to receptors containing three copies of the α 4 subunit that are potentiated. We exploited this observation to determine the regions required for the actions of physostigmine. Chimeric constructs of the α 2 and α 4 subunits located two regions in the extracellular amino-terminal domain of the subunit: the E loop (a loop of the transmitter-binding domain) and a region closer to the amino-terminus that collectively could completely determine the different effects of physostigmine. Point mutations then identified a single residue, α 2(I92) versus α 4(R92), that, when combined with transfer of the E loop, could convert the inhibition seen with α 2 subunits to potentiation and the potentiation seen with α 4 subunits to inhibition. In addition, other point mutations could affect the extent of potentiation or inhibition, indicating that a more extensive set of interactions in the amino-terminal domain plays some role in the actions of physostigmine.

molecular pharmacology

Determination of the Residues in the Extracellular Domain of the Nicotinic <i>α</i> Subunit Required for the Actions of Physostigmine on Neuronal Nicotinic Receptors

Determination of the Residues in the Extracellular Domain of the Nicotinic α Subunit Required for the Actions of Physostigmine on Neuronal Nicotinic Receptors