title: Differential neuronal localizations and dynamics of phosphorylated and unphosphorylated type 1 inositol 1,4,5-trisphosphate receptors.
abstract: Type 1 inositol 1,4,5-trisphosphate receptors are phosphorylated by cyclic-AMP-dependent protein kinase A at serines 1589 and 1755, with serine 1755 phosphorylation greatly predominating in the brain. Inositol 1,4,5-trisphosphate receptor protein kinase A phosphorylation augments Ca(2+) release. To assess type 1 protein kinase A phosphorylation dynamics in the intact organism, we developed antibodies selective for either serine 1755 phosphorylated or unphosphorylated species. Immunohistochemical studies reveal marked variation in localization. For example, in the hippocampus the phosphorylated type 1 inositol 1,4,5-trisphosphate receptor is restricted to CA1, while the unphosphorylated receptor occurs ubiquitously in CA1-CA3 and dentate gyrus granule cells. Throughout the brain the phosphorylated type 1 inositol 1,4,5-trisphosphate receptor is selectively enriched in dendrites, while the unphosphorylated receptor predominates in cell bodies. Focal cerebral ischemia in rats and humans is associated with dephosphorylation of type 1 inositol 1,4,5-trisphosphate receptors, and glutamatergic excitation of cerebellar Purkinje cells mediated by ibogaine elicits dephosphorylation of type 1 inositol 1,4,5-trisphosphate receptors that precedes evidence of excitotoxic neuronal degeneration. We have demonstrated striking variations in regional and subcellular distribution of inositol 1,4,5-trisphosphate receptor phosphorylation that may influence normal physiological intracellular Ca(2+) signaling in rat and human brain. We have further shown that the subcellular distribution of inositol 1,4,5-trisphosphate receptor phosphorylation in neurons is regulated by excitatory neurotransmission, as well as excitotoxic insult and neuronal ischemia-reperfusion. Phosphorylation dynamics of type 1 inositol 1,4,5-trisphosphate receptors may modulate intracellular Ca(2+) release and influence the cellular response to neurotoxic insults.
authors.affiliation: The Johns Hopkins University, School of Medicine, Department of Neuroscience, 725 N. Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Pieper
authors.forename: D J
authors.initials: DJ
authors.lastname: Brat
authors.forename: E
authors.initials: E
authors.lastname: O'Hearn
authors.forename: D K
authors.initials: DK
authors.lastname: Krug
authors.forename: A I
authors.initials: AI
authors.lastname: Kaplin
authors.forename: K
authors.initials: K
authors.lastname: Takahashi
authors.forename: J H
authors.initials: JH
authors.lastname: Greenberg
authors.forename: D
authors.initials: D
authors.lastname: Ginty
authors.forename: M E
authors.initials: ME
authors.lastname: Molliver
authors.forename: S H
authors.initials: SH
authors.lastname: Snyder
mesh_terms: D000328:Adult; D000818:Animals; D000918:Antibody Specificity; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D015220:Calcium Channels / Q000378:metabolism*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism; D005260:Female; D006801:Humans; D007050:Ibogaine / Q000633:toxicity; D007150:Immunohistochemistry; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008297:Male; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009928:Organ Specificity; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D011233:Precipitin Tests; D011689:Purkinje Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D005576:Colforsin; D007050:Ibogaine; D017868:Cyclic AMP-Dependent Protein Kinases