Figure 5.

Probe dependence as a consequence of a two-state model of allostery. (A) Cooperativity values for BQCA and different orthosteric agonists at the M₁ mAChR from cAMP accumulation assays (y axis values denote the fold increase in agonist potency in the presence of modulator). Acetylcholine (ACh) and carbachol (CCh) are high-efficacy agonists and are potentiated to a greater extent than the low-efficacy agonists pilocarpine and xanomeline. Thus, the degree of cooperativity is correlated with the intrinsic efficacy of each ligand. Data are replotted from Canals et al. (2012). (B) A speculative cartoon for a two-state model of allostery at the M₁ mAChR. High efficacy agonists have high cooperativity with PAMs by promoting a fully active conformation, indicated by a fully closed tyrosine lid. Low-efficacy agonists do not promote a fully active conformation, indicated by a partially closed tyrosine lid, and thus have lower cooperativity with BQCA.