Abstract

The α7 nicotinic acetylcholine receptors (nAChR) have been a puzzle since their discovery in brain and non-neuronal tissues. Maximal transient P_open of α7 nAChR with rapid agonist applications is only 0.002. The concentration dependence of α7 responses measured from stably transfected cells and Xenopus oocytes show the same disparity in potency estimations for peak currents and net charge, despite being studied at 1000-fold different time scales, in both cases the EC₅₀ for net charge was approximately 10-fold lower than for peak currents. The equivalence of the data obtained at such disparate time scales indicates that desensitization of α7 is nearly instantaneous. At high levels of agonist occupancy, the receptor is preferentially converted to a ligand-bound non-conducting state which can be destabilized by the positive allosteric modulator PNU-120596. Such currents can be sufficiently large to be cytotoxic to the α7-expressing cells. Both the potentiating effect of PNU-120596 and the associated cytotoxicity have a high temperature dependence that can be compensated for by serum factors. Therefore, despite reduced potentiation at body temperatures, use of type II positive allosteric modulators may put cells that naturally express high levels of α7 nAChR, such as neurons in the hippocampus and hypothalamus, at risk. With a low intrinsic open probability and high propensity toward the induction of non-conducting ligand-bound states, it is likely that the well-documented regulation of signal transduction pathways by α7 nAChR in cells such as those that regulate inflammation may be independent of ion channel activation and associated with the non-conducting conformational states.