title: Atypical calcium regulation of the PKD2-L1 polycystin ion channel.
abstract: Native PKD2-L1 channel subunits are present in primary cilia and other restricted cellular spaces. Here we investigate the mechanism for the channel's unusual regulation by external calcium, and rationalize this behavior to its specialized function. We report that the human PKD2-L1 selectivity filter is partially selective to calcium ions (Ca(2+)) moving into the cell, but blocked by high internal Ca(2+)concentrations, a unique feature of this transient receptor potential (TRP) channel family member. Surprisingly, we find that the C-terminal EF-hands and coiled-coil domains do not contribute to PKD2-L1 Ca(2+)-induced potentiation and inactivation. We propose a model in which prolonged channel activity results in calcium accumulation, triggering outward-moving Ca(2+) ions to block PKD2-L1 in a high-affinity interaction with the innermost acidic residue (D523) of the selectivity filter and subsequent long-term channel inactivation. This response rectifies Ca(2+) flow, enabling Ca(2+) to enter but not leave small compartments such as the cilium.
authors.affiliation: Department of Cardiology, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, United States.|Department of Neurobiology, Harvard Medical School, Boston, United States.
authors.forename: Paul G
authors.initials: PG
authors.lastname: DeCaen
authors.affiliation: Department of Cardiology, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, United States.|Department of Neurobiology, Harvard Medical School, Boston, United States.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, United States.|Department of Neurobiology, Harvard Medical School, Boston, United States.
authors.forename: Sunday
authors.initials: S
authors.lastname: Abiria
authors.affiliation: Department of Cardiology, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, United States.|Department of Neurobiology, Harvard Medical School, Boston, United States.
authors.forename: David E
authors.identifier: 0000-0002-4459-9428
authors.initials: DE
authors.lastname: Clapham
mesh_terms: D002118:Calcium / Q000378:metabolism*; D020832:EF Hand Motifs; D005786:Gene Expression Regulation; D006801:Humans; D017136:Ion Transport; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological
chemical_list: D008565:Membrane Proteins; C455507:PKD1L1 protein, human; D002118:Calcium
keywords: TRP channels; biophysics; calcium signaling; cell biology; channel desensitization; human; ion channel biophysics; ion selectivity; polycystic kidney disease; structural biology