title: p75 regulates Purkinje cell firing by modulating SK channel activity through Rac1.
abstract: p75 is expressed among Purkinje cells in the adult cerebellum, but its function has remained obscure. Here we report that p75 is involved in maintaining the frequency and regularity of spontaneous firing of Purkinje cells. The overall spontaneous firing activity of Purkinje cells was increased in p75(-/-) mice during the phasic firing period due to a longer firing period and accompanying reduction in silence period than in the wild type. We attribute these effects to a reduction in small conductance Ca(2+)-activated potassium (SK) channel activity in Purkinje cells from p75(-/-) mice compared with the wild type littermates. The mechanism by which p75 regulates SK channel activity appears to involve its ability to activate Rac1. In organotypic cultures of cerebellar slices, brain-derived neurotrophic factor increased RacGTP levels by activating p75 but not TrkB. These results correlate with a reduction in RacGTP levels in synaptosome fractions from the p75(-/-) cerebellum, but not in that from the cortex of the same animals, compared with wild type littermates. More importantly, we demonstrate that Rac1 modulates SK channel activity and firing patterns of Purkinje cells. Along with the finding that spine density was reduced in p75(-/-) cerebellum, these data suggest that p75 plays a role in maintaining normalcy of Purkinje cell firing in the cerebellum in part by activating Rac1 in synaptic compartments and modulating SK channels.
authors.affiliation: the Department of Neuroscience, Ohio State University, Columbus, Ohio 43210, the Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas 77030.
authors.forename: JinBin
authors.initials: J
authors.lastname: Tian
authors.affiliation: From the Department of Molecular and Cellular Biochemistry, the Biochemistry Program, and.
authors.forename: Chhavy
authors.initials: C
authors.lastname: Tep
authors.affiliation: From the Department of Molecular and Cellular Biochemistry.
authors.forename: Alex
authors.initials: A
authors.lastname: Benedick
authors.affiliation: From the Department of Molecular and Cellular Biochemistry.
authors.forename: Nabila
authors.initials: N
authors.lastname: Saidi
authors.affiliation: From the Department of Molecular and Cellular Biochemistry.
authors.forename: Jae Cheon
authors.initials: JC
authors.lastname: Ryu
authors.affiliation: From the Department of Molecular and Cellular Biochemistry.
authors.forename: Mi Lyang
authors.initials: ML
authors.lastname: Kim
authors.affiliation: the Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, and.
authors.forename: Shankar
authors.initials: S
authors.lastname: Sadasivan
authors.affiliation: the Biochemistry Program, and.
authors.forename: John
authors.initials: J
authors.lastname: Oberdick
authors.affiliation: the Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, and.
authors.forename: Richard
authors.initials: R
authors.lastname: Smeyne
authors.affiliation: the Department of Neuroscience, Ohio State University, Columbus, Ohio 43210, the Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas 77030 michael.x.zhu@uth.tmc.edu.
authors.forename: Michael X
authors.initials: MX
authors.lastname: Zhu
authors.affiliation: From the Department of Molecular and Cellular Biochemistry, sung.yoon@osumc.edu.
authors.forename: Sung Ok
authors.initials: SO
authors.lastname: Yoon
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000378:metabolism*; D004594:Electrophysiology; D006056:Golgi Apparatus / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009479:Neuropeptides / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011689:Purkinje Cells / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D019789:Tetraethylammonium / Q000737:chemistry; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020813:Receptor, trkB
chemical_list: D008562:Membrane Glycoproteins; D009479:Neuropeptides; D015221:Potassium Channels; D011505:Protein-Tyrosine Kinases; D017475:Receptors, Nerve Growth Factor; D051640:Small-Conductance Calcium-Activated Potassium Channels; D019789:Tetraethylammonium; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; C484602:Rac1 protein, mouse; C517634:Ngfr protein, mouse; C064371:Ntrk2 protein, mouse; D020813:Receptor, trkB
keywords: Brain-derived Neurotrophic Factor (BDNF); Cerebellum; Patch Clamp; Potassium Channel; Purkinje Cells; Rac1; SK Channels; p75 Neurotrophin Receptor