title: Energetics of cyclic AMP binding to HCN channel C terminus reveal negative cooperativity.
abstract: Cyclic AMP binds to the HCN channel C terminus and variably stabilizes its open state. Using isothermal titration calorimetry, we show that cAMP binds to one subunit of tetrameric HCN2 and HCN4 C termini with high affinity (∼0.12 μM) and subsequently with low affinity (∼1 μM) to the remaining three subunits. Changes induced by high affinity binding already exist in both a constrained HCN2 tetramer and the unconstrained HCN1 tetramer. Natural "preactivation" of HCN1 may explain both the smaller effect of cAMP on stabilizing its open state and the opening of unliganded HCN1, which occurs as though already disinhibited.
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Chow
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Filip
authors.initials: F
authors.lastname: Van Petegem
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. Electronic address: eaaccili@mail.ubc.ca.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Accili
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D011817:Rabbits; D012996:Solutions; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D020033:Protein Isoforms; D012996:Solutions; D000242:Cyclic AMP
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