Activation and desensitization of olfactory cAMP-gated channels. (A) Activation. Graphic representation of the C4L gating model according to Biskup et al. (2007) with identified contributions of individual channel subunits. Squares depict closed states, and circles represent open states of the channel. The subunit with the highest cAMP affinity, CNGA4, may bind the first cAMP molecule, and one CNGA2 subunit must bind the second. Filled signals indicate cAMP-liganded subunits. The arrow sizes represent preferred gating transitions. The red arrows in the shaded box around the doubly liganded state 3 indicate that opening transitions compete with the loss of one cAMP, whose dissociation is favored by a negative cooperativity effect. The binding of cAMP to the second CNGA2 and to CNGB1b (states 4 and 5) drives the channel to high levels of open probability at low cAMP concentrations. (B) Desensitization. The channel mostly operates at 1–6 μM cAMP with open probabilities <50%. In this state of weak activation, the binding of Ca²⁺ to the endogenous calmodulin (diamonds) causes channel closure, as the interaction of Ca²⁺ calmodulin with CNBGB1b reduces the cAMP sensitivity. The channel remains in this desensitized state until Ca²⁺ is extruded from the cilia.