title: RIC-3 phosphorylation enables dual regulation of excitation and inhibition of Caenorhabditis elegans muscle.
abstract: Brain function depends on a delicate balance between excitation and inhibition. Similarly, Caenorhabditis elegans motor system function depends on a precise balance between excitation and inhibition, as C. elegans muscles receive both inhibitory, GABAergic and excitatory, cholinergic inputs from motor neurons. Here we show that phosphorylation of the ER-resident chaperone of nicotinic acetylcholine receptors, RIC-3, leads to increased muscle excitability. RIC-3 phosphorylation at Ser-164 depends on opposing functions of the phosphatase calcineurin (TAX-6), and of the casein kinase II homologue KIN-10. Effects of calcineurin down-regulation and of phosphorylated RIC-3 on muscle excitability are mediated by GABAA receptor inhibition. Thus RIC-3 phosphorylation enables effects of this chaperone on GABAA receptors in addition to nAChRs. This dual effect provides coordinated regulation of excitation and inhibition and enables fine-tuning of the excitation-inhibition balance. Moreover, regulation of inhibitory GABAA signaling by calcineurin, a calcium- and calmodulin-dependent phosphatase, enables homeostatic balancing of excitation and inhibition.
authors.affiliation: Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Gracia
authors.initials: G
authors.lastname: Safdie
authors.affiliation: Buchmann Institute for Molecular Life Sciences and Institute of Biochemistry, Goethe-University, D-60438 Frankfurt, Germany.
authors.forename: Jana F
authors.initials: JF
authors.lastname: Liewald
authors.affiliation: Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kagan
authors.affiliation: Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Emil
authors.initials: E
authors.lastname: Battat
authors.affiliation: Buchmann Institute for Molecular Life Sciences and Institute of Biochemistry, Goethe-University, D-60438 Frankfurt, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gottschalk
authors.affiliation: Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel millet.treinin@mail.huji.ac.il.
authors.forename: Millet
authors.initials: M
authors.lastname: Treinin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D019703:Calcineurin / Q000378:metabolism*; D047390:Casein Kinase II / Q000378:metabolism; D056966:Excitation Contraction Coupling / Q000502:physiology; D018832:Molecular Chaperones / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D010766:Phosphorylation; D011978:Receptors, Nicotinic / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D018832:Molecular Chaperones; D011978:Receptors, Nicotinic; C454141:ric-3 protein, C elegans; D047390:Casein Kinase II; C000590648:Kin-10 protein, C elegans; D019703:Calcineurin