cAMP Control of HCN2 Channel Mg2+ Block Reveals Loose Coupling between the Cyclic Nucleotide-Gating Ring and the Pore
Figure 1
Schema and models describing HCN channel gating and Mg2+ block.
A. Mg2+ block of HCN channels may occur via a simple bi-molecular process (Scheme 1) or via more complex processes (e.g., Scheme 2). For further details see Methods, Results and Discussion. B. Schematic representation of an allosteric gating reaction wherein Mg2+ can bind to and block the open channel (reactions going back into the plane of the page) but does so without altering the energetics of either activation (horizontal steps in the plane of the page) or opening (vertical steps). Further details of the model and the methods used to optimize the rate constants associated with gating are given in the methods section. C. Schematic representation of the modular model of gating. Here, as in the basic concerted model shown in panel B, voltage sensors can activate irrespective of the status of the pore and the pore can open whether the voltage sensors are activated or not but voltage sensor activation and pore opening results in a reciprocal stabilization when the allosteric coupling factor, E is >1. Furthermore, tighter binding of agonist when the gating ring is activated leads to a reciprocal stabilization of the ring and bound agonist if the allosteric factor W is >1. The critical divergence between the concerted and modular models is that in the latter case elements of the gating ring can be either activated or deactivated when the pore is open. As shown, pore opening is coupled to the status of the C-linker such that the open pore and the activated C-linker are reciprocally stabilized when the coupling factor Q is >1. Coupling between other modules is not excluded [55] but is not required for, nor included in, our simulations.