What is the clinical evidence from this study?

Population: Hyperpolarization-activated cation currents. Intervention: ZD7288. Primary outcome: Mechanism of ZD7288 blockade and reversibility.

What question did this study set out to answer?

Investigate the molecular mechanism, voltage dependence, and structural determinants of ZD7288 blockade in cloned hyperpolarization-activated cation (Ih) channels.

January 16, 2001The Journal of General PhysiologyOpen Access

Blocker State Dependence and Trapping in Hyperpolarization-Activated Cation Channels

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Key result

ZD7288 blockade of I(h) channels requires channel opening and is mediated by residues in the pore-lining S6 region that are guarded by an intracellular activation gate.

Key Points

Investigate the molecular mechanism, voltage dependence, and structural determinants of ZD7288 blockade in cloned hyperpolarization-activated cation (Ih) channels.
Measured ionic currents using excised inside-out patch-clamp recordings on cloned mammalian mHCN1 and sea urchin SPIH channels.
Engineered mHCN1/SPIH chimeric channels and S6 triple point mutants to identify residues responsible for blocker reversibility and trapping.
ZD7288 blockade of mHCN1 required channel opening and was disfavored by strong hyperpolarization with an apparent valence of approximately 4.
Reversibility differences between mammalian mHCN1 and SPIH channels mapped to three pore-lining residues in the S6 region.
Channel closure in an S6 triple point mutant physically trapped ZD7288 within the pore behind an intracellular activation gate.

PICO

Population

Hyperpolarization-activated cation currents

Intervention / Comparator

ZD7288

Primary Outcome

Mechanism of ZD7288 blockade and reversibility

Discussion

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Implication

Advances molecular understanding of HCN pharmacology; leaves open whether gating-dependent blockade improves selective clinical targeting.

Cite This Study

Shin et al. (2001) studied Hyperpolarization-activated cation currents. ZD7288 was evaluated on Mechanism of ZD7288 blockade and reversibility. ZD7288 blockade of I(h) channels requires channel opening and is mediated by residues in the pore-lining S6 region that are guarded by an intracellular activation gate.

synapsesocial.com/papers/6a11be890765515418178a72 https://doi.org/10.1085/jgp.117.2.91

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Implication

Advances molecular understanding of HCN pharmacology; leaves open whether gating-dependent blockade improves selective clinical targeting.

Blocker State Dependence and Trapping in Hyperpolarization-Activated Cation Channels

Key Points

PICO

Discussion

Implication

Cite This Study

Blocker State Dependence and Trapping in Hyperpolarization-Activated Cation Channels

Key Points

PICO

Discussion

Implication

Cite This Study

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