Journal article
Tetramerization dynamics of the C-terminal domain underlies isoform-specific cAMP-gating in Hyperpolarization-activated Cyclic Nucleotide gated channels



Publication Details
Authors:
Lolicato, M.; Nardini, M.; Gazzarrini, S.; Möller, S.; Bertinetti, D.; Herberg, F.; Bolognesi, M.; Martin, H.; Fasolini, M.; Bertrand, J.; Arrigoni, C.; Thiel, G.; Moroni, A.
Publication year:
2011
Journal:
Journal of Biological Chemistry
Pages range:
44811–44820
Volume number:
286
ISSN:
0021-9258

Abstract
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 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 + CNBD) of the three isoforms. Our main finding is that tetramerization of the C-terminal domain of HCN1 occurs at basal cAMP concentrations while 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 V1/2 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.


Keywords
herberg

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