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J Biol Chem
2012 Nov 23;28748:40150-60. doi: 10.1074/jbc.M112.378513.
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A leucine zipper motif essential for gating of hyperpolarization-activated channels.
Wemhöner K
,
Silbernagel N
,
Marzian S
,
Netter MF
,
Rinné S
,
Stansfeld PJ
,
Decher N
.
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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.
Chen,
Functional roles of charged residues in the putative voltage sensor of the HCN2 pacemaker channel.
2000, Pubmed,
Xenbase
Chen,
Functional roles of charged residues in the putative voltage sensor of the HCN2 pacemaker channel.
2000,
Pubmed
,
Xenbase
Chen,
The S4-S5 linker couples voltage sensing and activation of pacemaker channels.
2001,
Pubmed
,
Xenbase
Chow,
Energetics of cyclic AMP binding to HCN channel C terminus reveal negative cooperativity.
2012,
Pubmed
Clayton,
Structure of the transmembrane regions of a bacterial cyclic nucleotide-regulated channel.
2008,
Pubmed
Decher,
Voltage-dependent gating of hyperpolarization-activated, cyclic nucleotide-gated pacemaker channels: molecular coupling between the S4-S5 and C-linkers.
2004,
Pubmed
,
Xenbase
DiFrancesco,
Pacemaker mechanisms in cardiac tissue.
1993,
Pubmed
Hulme,
A novel leucine zipper targets AKAP15 and cyclic AMP-dependent protein kinase to the C terminus of the skeletal muscle Ca2+ channel and modulates its function.
2002,
Pubmed
Hulme,
Beta-adrenergic regulation requires direct anchoring of PKA to cardiac CaV1.2 channels via a leucine zipper interaction with A kinase-anchoring protein 15.
2003,
Pubmed
Landschulz,
The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins.
1988,
Pubmed
Lolicato,
Tetramerization dynamics of C-terminal domain underlies isoform-specific cAMP gating in hyperpolarization-activated cyclic nucleotide-gated channels.
2011,
Pubmed
,
Xenbase
Long,
Crystal structure of a mammalian voltage-dependent Shaker family K+ channel.
2005,
Pubmed
Lu,
Coupling between voltage sensors and activation gate in voltage-gated K+ channels.
2002,
Pubmed
,
Xenbase
Ludwig,
A family of hyperpolarization-activated mammalian cation channels.
1998,
Pubmed
McCormack,
A role for hydrophobic residues in the voltage-dependent gating of Shaker K+ channels.
1991,
Pubmed
,
Xenbase
Männikkö,
Voltage-sensing mechanism is conserved among ion channels gated by opposite voltages.
2002,
Pubmed
,
Xenbase
Proenza,
Pacemaker channels produce an instantaneous current.
2002,
Pubmed
Proenza,
Distinct populations of HCN pacemaker channels produce voltage-dependent and voltage-independent currents.
2006,
Pubmed
Sali,
Comparative protein modelling by satisfaction of spatial restraints.
1993,
Pubmed
Sanguinetti,
Mutations of the S4-S5 linker alter activation properties of HERG potassium channels expressed in Xenopus oocytes.
1999,
Pubmed
,
Xenbase
Santoro,
Interactive cloning with the SH3 domain of N-src identifies a new brain specific ion channel protein, with homology to eag and cyclic nucleotide-gated channels.
1997,
Pubmed
Shin,
Inactivation in HCN channels results from reclosure of the activation gate: desensitization to voltage.
2004,
Pubmed
Syme,
Trafficking of the Ca2+-activated K+ channel, hIK1, is dependent upon a C-terminal leucine zipper.
2003,
Pubmed
Tristani-Firouzi,
Interactions between S4-S5 linker and S6 transmembrane domain modulate gating of HERG K+ channels.
2002,
Pubmed
,
Xenbase
Wahl-Schott,
HCN channels: structure, cellular regulation and physiological function.
2009,
Pubmed
Zerangue,
A new ER trafficking signal regulates the subunit stoichiometry of plasma membrane K(ATP) channels.
1999,
Pubmed
,
Xenbase
Zhong,
The heteromeric cyclic nucleotide-gated channel adopts a 3A:1B stoichiometry.
2002,
Pubmed
