Differential neuronal localizations and dynamics of phosphorylated and unphosphorylated type 1 inositol 1,4,5-trisphosphate receptors

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 p hosphorylation greatly predominating in the brain. Inositol 1,4,5-trisphosp hate receptor protein kinase A phosphorylation augments Ca2+ release. To as sess type 1 protein kinase A phosphorylation dynamics in the intact organis m, we developed antibodies selective for either serine 1755 phosphorylated or unphosphorylated species. Immunohistochemical studies reveal marked vari ation in localization. For example, in the hippocampus the phosphorylated t ype 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 u nphosphorylated receptor predominates in cell bodies. Focal cerebral ischem ia in rats and humans is associated with dephosphorylation of type 1 inosit ol 1,4,5-trisphosphate receptors, and glutamatergic excitation of cerebella r Purkinje cells mediated by ibogaine elicits dephosphorylation of type I i nositol 1,4,5-trisphosphate receptors that precedes evidence of excitotoxic neuronal degeneration. We have demonstrated striking variations in regiona l and subcellular distribution of inositol 1,4,5-trisphosphate receptor pho sphorylation that may influence normal physiological intracellular Ca2+ sig naling in rat and human brain. We have further shown that the subcellular d istribution of inositol 1,4,5-trisphosphate receptor phosphorylation in neu rons is regulated by excitatory neurotransmission, as well as excitotoxic i nsult and neuronal ischemia-reperfusion. Phosphorylation dynamics of type 1 inositol 1,4,5-trisphosphate receptors may modulate intracellular Ca2+ rel ease and influence the cellular response to neurotoxic insults. (C) 2001 IB RO. Published by Elsevier Science Ltd. All rights reserved.