Key result
Mutations in the highly conserved leucine zipper motif of the S5 segment in HCN channels resulted in loss of sensitivity to open upon hyperpolarization, indicating its essential role in channel gating.
The identification of a highly conserved leucine zipper motif in the S5 segment of HCN channels provides a crucial molecular mechanism for their unique hyperpolarization-activated gating behavior.
Reveals a key HCN gating motif in preclinical models; leaves open therapeutic targeting in human arrhythmias pending validation.
BACKGROUND: It is poorly understood how hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) function. RESULTS: We have identified a leucine zipper in the S5 segment of HCNs, regulating hyperpolarization-activated and instantaneous current components. CONCLUSION: The leucine zipper is essential for HCN channel gating. SIGNIFICANCE: The identification and functional characterization of the leucine zipper is an important step toward the understanding of HCN channel function. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are pacemakers in cardiac myocytes and neurons. Although their membrane topology closely resembles that of voltage-gated K(+) channels, the mechanism of their unique gating behavior in response to hyperpolarization is still poorly understood. We have identified a highly conserved leucine zipper motif in the S5 segment of HCN family members. In order to study the role of this motif for channel function, the leucine residues of the zipper were individually mutated to alanine, arginine, or glutamine residues. Leucine zipper mutants traffic to the plasma membrane, but the channels lose their sensitivity to open upon hyperpolarization. Thus, our data indicate that the leucine zipper is an important molecular determinant for hyperpolarization-activated channel gating. Residues of the leucine zipper interact with the adjacent S6 segment of the channel. This interaction is essential for voltage-dependent gating of the channel. The lower part of the leucine zipper, at the intracellular mouth of the channel, is important for stabilizing the closed state. Mutations at these sites increase current amplitudes or result in channels with deficient closing and increased min-P(o). Our data are further supported by homology models of the open and closed state of the HCN2 channel pore. Thus, we conclude that the leucine zipper of HCN channels is a major determinant for hyperpolarization-activated channel gating.
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Wemhöner et al. (2012) studied this question. Site-directed mutagenesis of leucine zipper motif in HCN channels vs. Wild-type HCN channels was evaluated on Channel gating and current amplitude upon hyperpolarization. Mutations in the highly conserved leucine zipper motif of the S5 segment in HCN channels resulted in loss of sensitivity to open upon hyperpolarization, indicating its essential role in channel gating.
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