title: Up-regulation of hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3) by specific interaction with K+ channel tetramerization domain-containing protein 3 (KCTD3).
abstract: Most ion channels consist of the principal ion-permeating core subunit(s) and accessory proteins that are assembled with the channel core. The biological functions of the latter proteins are diverse and include the regulation of the biophysical properties of the ion channel, its connection to signaling pathways and the control of its cell surface expression. There is recent evidence that native hyperpolarization-activated cyclic nucleotide-gated channel complexes (HCN1-4) also contain accessory subunits, among which TRIP8b (tetratricopeptide repeat-containing Rab8b-interacting protein) has been most extensively studied. Here, we identify KCTD3, a so far uncharacterized member of the potassium channel tetramerization-domain containing (KCTD) protein family as an HCN3-interacting protein. KCTD3 is widely expressed in brain and some non-neuronal tissues and colocalizes with HCN3 in specific regions of the brain including hypothalamus. Within the HCN channel family, KCTD3 specifically binds to HCN3 and leads to a profound up-regulation of cell surface expression and current density of this channel. HCN3 can also functionally interact with TRIP8b; however, we found no evidence for channel complexes containing both TRIP8b and KCTD3. The C terminus of HCN3 is crucially required for functional interaction with KCTD3. Replacement of the cytosolic C terminus of HCN2 by the corresponding domain of HCN3 renders HCN2 sensitive to regulation by KCTD3. The C-terminal-half of KCTD3 is sufficient for binding to HCN3. However, the complete protein including the N-terminal tetramerization domain is needed for HCN3 current up-regulation. Together, our experiments indicate that KCTD3 is an accessory subunit of native HCN3 complexes.
authors: Center for Integrated Protein Science CIPS-M and Zentrum für Pharmaforschung, Department Pharmazie, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors: Xiaochun
authors: X
authors: Cao-Ehlker
authors: Center for Integrated Protein Science CIPS-M and Zentrum für Pharmaforschung, Department Pharmazie, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors: Xiangang
authors: X
authors: Zong
authors: Center for Integrated Protein Science CIPS-M and Zentrum für Pharmaforschung, Department Pharmazie, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors: Verena
authors: V
authors: Hammelmann
authors: Center for Integrated Protein Science CIPS-M and Zentrum für Pharmaforschung, Department Pharmazie, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors: Christian
authors: C
authors: Gruner
authors: Center for Integrated Protein Science CIPS-M and Zentrum für Pharmaforschung, Department Pharmazie, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors: Stefanie
authors: S
authors: Fenske
authors: Center for Integrated Protein Science CIPS-M and Zentrum für Pharmaforschung, Department Pharmazie, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors: Stylianos
authors: S
authors: Michalakis
authors: Center for Integrated Protein Science CIPS-M and Zentrum für Pharmaforschung, Department Pharmazie, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors: Christian
authors: C
authors: Wahl-Schott
authors: Center for Integrated Protein Science CIPS-M and Zentrum für Pharmaforschung, Department Pharmazie, Ludwig-Maximilians-Universität München, 81377 Munich, Germany. Electronic address: martin.biel@cup.uni-muenchen.de.
authors: Martin
authors: M
authors: Biel
mesh_terms: D000818:Animals; D001703:Biophysics / Q000379:methods; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004594:Electrophysiology / Q000379:methods; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D057809:HEK293 Cells; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007031:Hypothalamus / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D018408:Patch-Clamp Techniques; D010802:Phylogeny; D015221:Potassium Channels / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D020798:Two-Hybrid System Techniques; D015854:Up-Regulation
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; C472018:HCN3 protein, human; C578669:HCN3 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; C581029:KCTD3 protein, human; C581028:KCTD3 protein, mouse; D015221:Potassium Channels
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