1型肌醇1,4,5-三磷酸受体磷酸化和未磷酸化形式的差异性神经元定位及动态变化

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

作者信息

Pieper A A, Brat D J, O'Hearn E, Krug D K, Kaplin A I, Takahashi K, Greenberg J H, Ginty D, Molliver M E, Snyder S H

机构信息

The Johns Hopkins University, School of Medicine, Department of Neuroscience, 725 N. Wolfe Street, Baltimore, MD 21205, USA.

出版信息

Neuroscience. 2001;102(2):433-44. doi: 10.1016/s0306-4522(00)00470-x.

DOI:10.1016/s0306-4522(00)00470-x

PMID:11166129

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.

摘要

1型肌醇1,4,5 -三磷酸受体在丝氨酸1589和1755处被环磷酸腺苷依赖性蛋白激酶A磷酸化，其中丝氨酸1755磷酸化在大脑中占主导地位。肌醇1,4,5 -三磷酸受体蛋白激酶A磷酸化增强了Ca(2+)释放。为了评估完整生物体中1型蛋白激酶A的磷酸化动力学，我们开发了对丝氨酸1755磷酸化或未磷酸化形式具有选择性的抗体。免疫组织化学研究揭示了定位上的显著差异。例如，在海马体中，磷酸化的1型肌醇1,4,5 -三磷酸受体局限于CA1区，而未磷酸化的受体在CA1 - CA3区和齿状回颗粒细胞中普遍存在。在整个大脑中，磷酸化的1型肌醇1,4,5 -三磷酸受体在树突中选择性富集，而未磷酸化的受体在细胞体中占主导地位。大鼠和人类的局灶性脑缺血与1型肌醇1,4,5 -三磷酸受体的去磷酸化有关，由伊博格碱介导的小脑浦肯野细胞的谷氨酸能兴奋引发1型肌醇1,4,5 -三磷酸受体的去磷酸化，这早于兴奋性毒性神经元变性的证据。我们已经证明了肌醇1,4,5 -三磷酸受体磷酸化在区域和亚细胞分布上的显著差异，这可能会影响大鼠和人类大脑中正常的生理细胞内Ca(2+)信号传导。我们进一步表明，神经元中肌醇1,4,5 -三磷酸受体磷酸化的亚细胞分布受兴奋性神经传递以及兴奋性毒性损伤和神经元缺血再灌注的调节。1型肌醇1,4,5 -三磷酸受体的磷酸化动力学可能调节细胞内Ca(2+)释放并影响细胞对神经毒性损伤的反应。