{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T06:10:55Z","timestamp":1775542255211,"version":"3.50.1"},"reference-count":39,"publisher":"Proceedings of the National Academy of Sciences","issue":"40","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2014,10,7]]},"abstract":"<jats:title>Significance<\/jats:title>\n          <jats:p>cAMP regulation of ion channels controls higher brain functions, such as sleep, memory, and cognition. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are activated by the direct binding of cAMP to their cytoplasmic tail and inhibited by the neuronal \u03b2-subunit tetratricopeptide repeat-containing Rab8b interacting protein (TRIP8b), which prevents cAMP binding. Understanding the molecular mechanisms of regulation of this family of ion channels is critical because it pertains to the physiological processes and diseases associated with dysfunctions in the HCN current. Here, we explain the dual regulatory system of HCN2 channels in atomic detail. cAMP and TRIP8b do not compete for the same binding site on the HCN2 cytoplasmic tail; rather, they exert their mutual competition by promoting and stabilizing two different conformational states of the protein.<\/jats:p>","DOI":"10.1073\/pnas.1410389111","type":"journal-article","created":{"date-parts":[[2014,9,3]],"date-time":"2014-09-03T03:56:19Z","timestamp":1409716579000},"page":"14577-14582","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":72,"title":["Structural basis for the mutual antagonism of cAMP and TRIP8b in regulating HCN channel function"],"prefix":"10.1073","volume":"111","author":[{"given":"Andrea","family":"Saponaro","sequence":"first","affiliation":[{"name":"Department of Biosciences, University of Milan, 20133 Milan, Italy;"}]},{"given":"Sofia R.","family":"Pauleta","sequence":"additional","affiliation":[{"name":"Rede de Qu\u00edmica e Tecnologia\/Centro de Qu\u00edmica Fina e Biotecnologia (REQUIMTE\/CQFB), Departamento de Qu\u00edmica, Faculdade de Ci\u00eancias e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal;"}]},{"given":"Francesca","family":"Cantini","sequence":"additional","affiliation":[{"name":"Centro Risonanze Magnetiche (CERM) and Departement of Chemistry, University of Florence, 50019 Sesto Fiorentino, Italy;"}]},{"given":"Manolis","family":"Matzapetakis","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal;"}]},{"given":"Christian","family":"Hammann","sequence":"additional","affiliation":[{"name":"School of Engineering and Science, Molecular Life Sciences Research Center, Jacobs University Bremen, DE-28759 Bremen, Germany;"}]},{"given":"Chiara","family":"Donadoni","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan, 20133 Milan, Italy;"}]},{"given":"Lei","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Columbia University, New York, NY 10032; and"}]},{"given":"Gerhard","family":"Thiel","sequence":"additional","affiliation":[{"name":"Membrane Biophysics, Technical University of Darmstadt, 64287 Darmstadt, Germany"}]},{"given":"Lucia","family":"Banci","sequence":"additional","affiliation":[{"name":"Centro Risonanze Magnetiche (CERM) and Departement of Chemistry, University of Florence, 50019 Sesto Fiorentino, Italy;"}]},{"given":"Bina","family":"Santoro","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Columbia University, New York, NY 10032; and"}]},{"given":"Anna","family":"Moroni","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan, 20133 Milan, Italy;"}]}],"member":"341","published-online":{"date-parts":[[2014,9,2]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1152\/physrev.00029.2008","article-title":"Hyperpolarization-activated cation channels: From genes to function","volume":"89","author":"Biel M","year":"2009","unstructured":"M Biel, C Wahl-Schott, S Michalakis, X Zong, Hyperpolarization-activated cation channels: From genes to function. 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