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Tetramerization dynamics of C-terminal domain underlies isoform-specific cAMP gating in hyperpolarization-activated cyclic nucleotide-gated channels.
J Biol Chem. 2011 Dec 30; 286(52):44811-20.JB

Abstract

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are dually activated by hyperpolarization and binding of cAMP to their cyclic nucleotide binding domain (CNBD). HCN isoforms respond differently to cAMP; binding of cAMP shifts activation of HCN2 and HCN4 by 17 mV but shifts that of HCN1 by only 2-4 mV. To explain the peculiarity of HCN1, we solved the crystal structures and performed a biochemical-biophysical characterization of the C-terminal domain (C-linker plus CNBD) of the three isoforms. Our main finding is that tetramerization of the C-terminal domain of HCN1 occurs at basal cAMP concentrations, whereas those of HCN2 and HCN4 require cAMP saturating levels. Therefore, HCN1 responds less markedly than HCN2 and HCN4 to cAMP increase because its CNBD is already partly tetrameric. This is confirmed by voltage clamp experiments showing that the right-shifted position of V(½) in HCN1 is correlated with its propensity to tetramerize in vitro. These data underscore that ligand-induced CNBD tetramerization removes tonic inhibition from the pore of HCN channels.

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Authors+Show Affiliations

Lolicato M
Department of Biology and Consiglio Nazionale delle Ricerche-Istituto di Biofisica, University of Milan, Via Celoria 26, 20133 Milan, Italy.
Nardini M
No affiliation info available
Gazzarrini S
No affiliation info available
Möller S
No affiliation info available
Bertinetti D
No affiliation info available
Herberg FW
No affiliation info available
Bolognesi M
No affiliation info available
Martin H
No affiliation info available
Fasolini M
No affiliation info available
Bertrand JA
No affiliation info available
Arrigoni C
No affiliation info available
Thiel G
No affiliation info available
Moroni A
No affiliation info available

MeSH

AnimalsCyclic AMPHumansHyperpolarization-Activated Cyclic Nucleotide-Gated ChannelsIon Channel GatingIon ChannelsOocytesPotassium ChannelsProtein IsoformsProtein MultimerizationProtein Structure, TertiaryXenopus laevis

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22006928

Citation

Lolicato, Marco, et al. "Tetramerization Dynamics of C-terminal Domain Underlies Isoform-specific cAMP Gating in Hyperpolarization-activated Cyclic Nucleotide-gated Channels." The Journal of Biological Chemistry, vol. 286, no. 52, 2011, pp. 44811-20.
Lolicato M, Nardini M, Gazzarrini S, et al. Tetramerization dynamics of C-terminal domain underlies isoform-specific cAMP gating in hyperpolarization-activated cyclic nucleotide-gated channels. J Biol Chem. 2011;286(52):44811-20.
Lolicato, M., Nardini, M., Gazzarrini, S., Möller, S., Bertinetti, D., Herberg, F. W., Bolognesi, M., Martin, H., Fasolini, M., Bertrand, J. A., Arrigoni, C., Thiel, G., & Moroni, A. (2011). Tetramerization dynamics of C-terminal domain underlies isoform-specific cAMP gating in hyperpolarization-activated cyclic nucleotide-gated channels. The Journal of Biological Chemistry, 286(52), 44811-20. https://doi.org/10.1074/jbc.M111.297606
Lolicato M, et al. Tetramerization Dynamics of C-terminal Domain Underlies Isoform-specific cAMP Gating in Hyperpolarization-activated Cyclic Nucleotide-gated Channels. J Biol Chem. 2011 Dec 30;286(52):44811-20. PubMed PMID: 22006928.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tetramerization dynamics of C-terminal domain underlies isoform-specific cAMP gating in hyperpolarization-activated cyclic nucleotide-gated channels. AU - Lolicato,Marco, AU - Nardini,Marco, AU - Gazzarrini,Sabrina, AU - Möller,Stefan, AU - Bertinetti,Daniela, AU - Herberg,Friedrich W, AU - Bolognesi,Martino, AU - Martin,Holger, AU - Fasolini,Marina, AU - Bertrand,Jay A, AU - Arrigoni,Cristina, AU - Thiel,Gerhard, AU - Moroni,Anna, Y1 - 2011/10/17/ PY - 2011/10/19/entrez PY - 2011/10/19/pubmed PY - 2012/3/1/medline SP - 44811 EP - 20 JF - The Journal of biological chemistry JO - J Biol Chem VL - 286 IS - 52 N2 - Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are dually activated by hyperpolarization and binding of cAMP to their cyclic nucleotide binding domain (CNBD). HCN isoforms respond differently to cAMP; binding of cAMP shifts activation of HCN2 and HCN4 by 17 mV but shifts that of HCN1 by only 2-4 mV. To explain the peculiarity of HCN1, we solved the crystal structures and performed a biochemical-biophysical characterization of the C-terminal domain (C-linker plus CNBD) of the three isoforms. Our main finding is that tetramerization of the C-terminal domain of HCN1 occurs at basal cAMP concentrations, whereas those of HCN2 and HCN4 require cAMP saturating levels. Therefore, HCN1 responds less markedly than HCN2 and HCN4 to cAMP increase because its CNBD is already partly tetrameric. This is confirmed by voltage clamp experiments showing that the right-shifted position of V(½) in HCN1 is correlated with its propensity to tetramerize in vitro. These data underscore that ligand-induced CNBD tetramerization removes tonic inhibition from the pore of HCN channels. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/22006928/Tetramerization_dynamics_of_C_terminal_domain_underlies_isoform_specific_cAMP_gating_in_hyperpolarization_activated_cyclic_nucleotide_gated_channels_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)65529-6 DB - PRIME DP - Unbound Medicine ER -