Integrated allosteric model of voltage gating of HCN channels.

摘要: Hyperpolarization-activated (pacemaker) channels are dually gated by negative voltage and intracellular cAMP. Kinetics of native cardiac f-channels not compatible with HH gating, require closed/open multistate models. We verified that members the HCN channel family (mHCN1, hHCN2, hHCN4) also have properties complying such as sigmoidal activation deactivation, deviating from fixed power an exponential, removal “delay” preconditioning hyperpolarization. Previous work on has indicated shifting action cAMP open probability (Po) curve can be accounted for allosteric model, whereby binds more favorably to than closed channels. therefore asked whether only cAMP-dependent, but voltage-dependent gating hyperpolarization-activated could explained model. hypothesized tetramers each subunit comprises a sensor moving between “reluctant” “willing” states, whereas sensors independently voltage, transitions occur allosterically. These hypotheses led scheme comprising five states. estimated model rate constants fitting first delay curves single exponential time constant curves, then individual activation/deactivation traces. By simply using different sets constants, accounts qualitative quantitative aspects all three isoforms investigated, allows interpretation kinetic isoforms. For example, faster kinetics HCN1 relative HCN2/HCN4 attributable higher sensors' rates looser voltage-independent interactions subunits in transitions. It experimental evidence reduction positive charge leads shifts Po curve, little change slope. thus involves two processes: opening/closing.