Complex allosteric effects of amiodarone at M 1 muscarinic receptors: signal sharpening

We have previously reported that amiodarone interacts with a novel allosteric site on muscarinic receptors. At the M 3 and M 5 subtypes, the major effect of amiodarone is to enhance the maximal degree of response elicited by acetylcholine and other agonists, without significantly altering the potency of the agonist. The initial screening of the M 1 subtype, at typical (EC 20 ‐EC 50 ) concentrations of agonist, revealed no effect of amiodarone. In the present study, we demonstrate that amiodarone does in fact enhance the maximal agonist effect at M 1 , but that a concomitant decrease in agonist potency obscures the effect at the screening concentrations of agonist that were previously used. These effects, at all three subtypes, are well‐explained as an interaction between the parameters for binding cooperativity and activation cooperativity in Hall's allosteric two‐state model (Mol Pharmacol 58 :1412). Furthermore, the effects of amiodarone on M 1 receptor signaling illustrate the possibility of a new form of receptor modulation; we have named this modulation “ signal sharpening ”. The effect of signal sharpening occurs in the sense that responses above a certain magnitude are enhanced, while responses below that magnitude are reduced. We speculate that one way this type of modulation may be useful would be in regulating the contribution of transmitter spillover to extra‐synaptic signaling. [Supported by PHS R01 05214]