title: Disruption of polycystin-L causes hippocampal and thalamocortical hyperexcitability.
abstract: Epilepsy or seizure disorder is among the least understood chronic medical conditions affecting over 65 million people worldwide. Here, we show that disruption of the polycystic kidney disease 2-like 1 (Pkd2l1 or Pkdl), encoding polycystin-L (PCL), a non-selective cation channel, increases neuronal excitability and the susceptibility to pentylenetetrazol-induced seizure in mice. PCL interacts with β2-adrenergic receptor (β2AR) and co-localizes with β2AR on the primary cilia of neurons in the brain. Pkdl deficiency leads to the loss of β2AR on neuronal cilia, which is accompanied with a remarkable reduction in cAMP levels in the central nervous system (CNS). The reduction of cAMP levels is associated with a reduction in the activation of cAMP response element-binding protein, but not the activation of Ca(2+)/calmodulin-dependent protein kinase II, Akt or mitogen-activated protein kinases. Our data, thus, indicate for the first time that a ciliary protein complex is required for the control of neuronal excitability in the CNS.
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Room 522, 4 Blackfan Circle, Boston, MA 02115, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Yao
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Room 522, 4 Blackfan Circle, Boston, MA 02115, USA, Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, P.R. China and.
authors.forename: Chong
authors.initials: C
authors.lastname: Luo
authors.affiliation: Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Harvey
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Room 522, 4 Blackfan Circle, Boston, MA 02115, USA.
authors.forename: Maoqing
authors.initials: M
authors.lastname: Wu
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Room 522, 4 Blackfan Circle, Boston, MA 02115, USA.
authors.forename: Taylor H
authors.initials: TH
authors.lastname: Schreiber
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Room 522, 4 Blackfan Circle, Boston, MA 02115, USA, Department of Acupuncture and Moxibustion, Hubei University of Chinese Medicine, Hubei, P.R., China.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Du
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Room 522, 4 Blackfan Circle, Boston, MA 02115, USA.
authors.forename: Nuria
authors.initials: N
authors.lastname: Basora
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Room 522, 4 Blackfan Circle, Boston, MA 02115, USA.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Su
authors.affiliation: Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Contreras
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Room 522, 4 Blackfan Circle, Boston, MA 02115, USA, zhou@rics.bwh.harvard.edu.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000172:deficiency / Q000235:genetics*; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D002923:Cilia / Q000378:metabolism / Q000473:pathology; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004827:Epilepsy / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019706:Excitatory Postsynaptic Potentials; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D017136:Ion Transport; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010433:Pentylenetetrazole; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D013788:Thalamus / Q000378:metabolism* / Q000473:pathology
chemical_list: D015220:Calcium Channels; D017362:Cyclic AMP Response Element-Binding Protein; C486487:Pkd2l1 protein, mouse; D018343:Receptors, Adrenergic, beta-2; D011956:Receptors, Cell Surface; D000242:Cyclic AMP; D010433:Pentylenetetrazole