Abstract
Modulating the activity of ion channels by blockers yields information on both the mode of drug action and on the biophysics of ion transport. Here we investigate the interplay between ions in the selectivity filter (SF) of K+ channels and the release kinetics of the blocker tetrapropylammonium in the model channel KcvNTS. A quantitative expression calculates blocker release rate constants directly from voltage-dependent ion occupation probabilities in the SF. The latter are obtained by a kinetic model of single-channel currents recorded in the absence of the blocker. The resulting model contains only two adjustable parameters of ion-blocker interaction and holds for both symmetric and asymmetric ionic conditions. This data-derived model is corroborated by 3D reference interaction site model (3D RISM) calculations on several model systems, which show that the K+ occupation probability is unaffected by the blocker, a direct consequence of the strength of the ion-carbonyl attraction in the SF, independent of the specific protein background. Hence, KcvNTS channel blocker release kinetics can be reduced to a small number of system-specific parameters. The pore-independent asymmetric interplay between K+ and blocker ions potentially allows for generalizing these results to similar potassium channels.
Highlights
Ion channels are crucial for many cellular functions and important drug targets (Ashcroft, 2006; Bernard and Shevell, 2008; Fernández-Ballester et al, 2011; Bagal et al, 2013)
It is well established that quaternary ammonium ions occlude the selectivity filter from the cytosolic side (FaraldoGómez et al, 2007; Lenaeus et al, 2014; Figure 1E)
Because of the strong conservation of the canonical selectivity filter sequence throughout potassium channels in all realms of life (Heginbotham et al, 1994; Figure 1D), it is expected that the observed effects ought to be fairly similar throughout the whole K+ channel family
Summary
Ion channels are crucial for many cellular functions and important drug targets (Ashcroft, 2006; Bernard and Shevell, 2008; Fernández-Ballester et al, 2011; Bagal et al, 2013). A major class of drugs for potassium (K+) channels are pore blockers that bind in the aqueous cavity between selectivity filter and intracellular pore entrance. Many of these molecules are either positively. Asymmetric Channel Blocker/Ion Interplay charged (Sánchez-Chapula et al, 2002) or bind with a positively charge moiety oriented towards the selectivity filter (Bucchi et al, 2013; Du et al, 2014). Examples are the heart rate-reducing agent ivabradine for HCN channels (Bucchi et al, 2013), and drugs blocking hERG channels either as a desired effect (e.g., the antiarrhythmic ranolazine, Du et al, 2014) or as an unwanted side effect, like Chloroquine (Sánchez-Chapula et al, 2002). To facilitate the development of new compounds, a profound understanding of the molecular interactions between the blocker, the channel protein, and the permeating ions is essential
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