Molecular Regulation and Pharmacology of Pacemaker Channels

Bois, Patrick; Guinamard, Romain; Chemaly, Antoun El; Faivré, Jean-François; Bescond, Jocelyn

doi:10.2174/138161207781368729

Cited by 22 publications

(4 citation statements)

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“…In good agreement with the findings of earlier studies [16,33,34], the present observations disclosed that the presence of CIL was able to suppress the amplitude of hyperpolarization-elicited I h , as well as to slow the rate of the current activation (Figure 1). There was a distinct hyperpolarizing shift in the midpoint of the activation curve of I h in its presence with no alterations in the gating charge of the current (Figure 1).…”

Section: Discussionsupporting

confidence: 93%

Inhibitory Effective Perturbations of Cilobradine (DK-AH269), A Blocker of HCN Channels, on the Amplitude and Gating of Both Hyperpolarization-Activated Cation and Delayed-Rectifier Potassium Currents

2020

IJMS

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Cilobradine (CIL, DK-AH269), an inhibitor of hyperpolarization-activated cation current (Ih), has been observed to possess pro-arrhythmic properties. Whether and how CIL is capable of perturbing different types of membrane ionic currents existing in electrically excitable cells, however, is incompletely understood. In this study, we intended to examine possible modifications by it or other structurally similar compounds of ionic currents in pituitary tumor (GH3) cells and in heart-derived H9c2 cells. The standard whole-cell voltage-clamp technique was performed to examine the effect of CIL on ionic currents. GH3-cell exposure to CIL suppressed the density of hyperpolarization-evoked Ih in a concentration-dependent manner with an effective IC50 of 3.38 μM. Apart from its increase in the activation time constant of Ih during long-lasting hyperpolarization, the presence of CIL (3 μM) distinctly shifted the steady-state activation curve of Ih triggered by a 2-s conditioning pulse to a hyperpolarizing direction by 10 mV. As the impedance-frequency relation of Ih was studied, its presence raised the impedance magnitude at the resonance frequency induced by chirp voltage. CIL also suppressed delayed-rectifier K+ current (IK(DR)) followed by the accelerated inactivation time course of this current, with effective IC50 (measured at late IK(DR)) or KD value of 3.54 or 3.77 μM, respectively. As the CIL concentration increased 1 to 3 μM, the inactivation curve of IK(DR) elicited by 1- or 10-s conditioning pulses was shifted to a hyperpolarizing potential by approximately 10 mV, and the recovery of IK(DR) inactivation during its presence was prolonged. The peak Na+ current (INa) during brief depolarization was resistant to being sensitive to the presence of CIL, yet to be either decreased by subsequent addition of A-803467 or enhanced by that of tefluthrin. In cardiac H9c2 cells, unlike the CIL effect, the addition of either ivabradine or zatebradine mildly led to a lowering in IK(DR) amplitude with no conceivable change in the inactivation time course of the current. Taken together, the compound like CIL, which was tailored to block hyperpolarization-activated cation (HCN) channels effectively, was also capable of altering the amplitude and gating of IK(DR), thereby influencing the functional activities of electrically excitable cells, such as GH3 cells.

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Section: Discussionsupporting

confidence: 93%

Inhibitory Effective Perturbations of Cilobradine (DK-AH269), A Blocker of HCN Channels, on the Amplitude and Gating of Both Hyperpolarization-Activated Cation and Delayed-Rectifier Potassium Currents

2020

IJMS

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“…[193]) is controversial. New evidence in favor to a direct binding of genistein to the channel comes from a recent paper by Rozario et al [194], where the effect of genistein was measured on wt mHCN1 and mHCN2 and on mutants where a critical arginine in the CNBD has been replaced with glutamate (mHCN1-R538E and mHCN2-R591E).…”

Section: Substances That Have Been Shown To Modulate Hcn Channel Actimentioning

confidence: 99%

HCN Channels Modulators: The Need for Selectivity

Romanelli

Sartiani²,

Masi³

et al. 2016

CTMC

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Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, the molecular correlate of the hyperpolarization-activated current (I f /I h ), are membrane proteins which play an important role in several physiological processes and various pathological conditions. In the Sino Atrial Node (SAN) HCN4 is the target of ivabradine, a bradycardic agent that is, at the moment, the only drug which specifically blocks I f . Nevertheless, several other pharmacological agents have been shown to modulate HCN channels, a property that may contribute to their therapeutic activity and/or to their side effects.HCN channels are considered potential targets for developing drugs to treat several important pathologies, but a major issue in this field is the discovery of isoform-selective compounds, owing to the wide distribution of these proteins into the central and peripheral nervous systems, heart and other peripheral tissues. This survey is focused on the compounds that have been shown, or have been designed, to interact with HCN channels and on their binding sites, with the aim to summarize current knowledge and possibly to unveil useful information to design new potent and selective modulators.

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“…The pacemaker activity of sinoatrial node (SAN) cells in the mammalian heart arises from the integrated action of multiple sarcolemmal ionic channel currents and the interaction between the intracellular calcium handling and sarcolemmal electrogenic processes (Irisawa et al, 1993;Mangoni and Nargeot, 2008;Lakatta et al, 2010). The hyperpolarization-activated "funny" current, I f , present in the SAN and other regions of the cardiac conduction system (Boyett, 2009;Difrancesco, 2010), is produced by the hyperpolarization-activated cyclic nucleotide gated (HCN) channel isoforms (of which there are four: HCN1-4), each of which is comprised of six transmembrane domains with four subunits combining to produce functional tetrameric channels, as occurs for voltage-gated potassium channels (Bois et al, 2007;Difrancesco, 2010). Previous studies of the rabbit SAN have shown that although HCN isoforms 1, 2, and 4 are all expressed in the heart, HCN4 is the most abundant in the SAN and the I f density within SAN sub-regions correlates strongly with HCN4 expression levels (Thollon et al, 2007;Brioschi et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

The Functional Role of Hyperpolarization Activated Current (If) on Cardiac Pacemaking in Human vs. in the Rabbit Sinoatrial Node: A Simulation and Theoretical Study

et al. 2021

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The cardiac hyperpolarization-activated “funny” current (If), which contributes to sinoatrial node (SAN) pacemaking, has a more negative half-maximal activation voltage and smaller fully-activated macroscopic conductance in human than in rabbit SAN cells. The consequences of these differences for the relative roles of If in the two species, and for their responses to the specific bradycardic agent ivabradine at clinical doses have not been systematically explored. This study aims to address these issues, through incorporating rabbit and human If formulations developed by Fabbri et al. into the Severi et al. model of rabbit SAN cells. A theory was developed to correlate the effect of If reduction with the total inward depolarising current (Itotal) during diastolic depolarization. Replacing the rabbit If formulation with the human one increased the pacemaking cycle length (CL) from 355 to 1,139 ms. With up to 20% If reduction (a level close to the inhibition of If by ivabradine at clinical concentrations), a modest increase (~5%) in the pacemaking CL was observed with the rabbit If formulation; however, the effect was doubled (~12.4%) for the human If formulation, even though the latter has smaller If density. When the action of acetylcholine (ACh, 0.1 nM) was considered, a 20% If reduction markedly increased the pacemaking CL by 37.5% (~27.3% reduction in the pacing rate), which is similar to the ivabradine effect at clinical concentrations. Theoretical analysis showed that the resultant increase of the pacemaking CL is inversely proportional to the magnitude of Itotal during diastolic depolarization phase: a smaller If in the model resulted in a smaller Itotal amplitude, resulting in a slower pacemaking rate; and the same reduction in If resulted in a more significant change of CL in the cell model with a smaller Itotal. This explained the mechanism by which a low dose of ivabradine slows pacemaking rate more in humans than in the rabbit. Similar results were seen in the Fabbri et al. model of human SAN cells, suggesting our observations are model-independent. Collectively, the results of study explain why low dose ivabradine at clinically relevant concentrations acts as an effective bradycardic agent in modulating human SAN pacemaking.

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Molecular Regulation and Pharmacology of Pacemaker Channels

Cited by 22 publications

References 100 publications

Inhibitory Effective Perturbations of Cilobradine (DK-AH269), A Blocker of HCN Channels, on the Amplitude and Gating of Both Hyperpolarization-Activated Cation and Delayed-Rectifier Potassium Currents

Inhibitory Effective Perturbations of Cilobradine (DK-AH269), A Blocker of HCN Channels, on the Amplitude and Gating of Both Hyperpolarization-Activated Cation and Delayed-Rectifier Potassium Currents

HCN Channels Modulators: The Need for Selectivity

The Functional Role of Hyperpolarization Activated Current (If) on Cardiac Pacemaking in Human vs. in the Rabbit Sinoatrial Node: A Simulation and Theoretical Study

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