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Regulation of Calcium-Independent Phospholipase A2 Expression by Adrenoceptors and Sterol Regulatory Element Binding Protein—Potential Crosstalk Between Sterol and Glycerophospholipid Mediators

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Abstract

Calcium-independent phospholipase A2 (iPLA2) is an 85-kDa enzyme that releases docosahexaenoic acid (DHA) from glycerophospholipids. DHA can be metabolized to resolvins and neuroprotectins that have anti-inflammatory properties and effects on neural plasticity. Recent studies show an important role of prefrontal cortical iPLA2 in hippocampo-prefrontal cortical LTP and antidepressant-like effect of the norepinephrine reuptake inhibitor (NRI) antidepressant, maprotiline. In this study, we elucidated the cellular mechanisms through which stimulation of adrenergic receptors could lead to increased iPLA2 expression. Treatment of SH-SY5Y neuroblastoma cells with maprotiline, another tricyclic antidepressant with noradrenaline reuptake inhibiting properties, nortriptyline, and the adrenergic receptor agonist, phenylephrine, resulted in increased iPLA2β mRNA expression. This increase was blocked by inhibitors to alpha-1 adrenergic receptor, mitogen-activated protein (MAP) kinase or extracellular signal-regulated kinase (ERK) 1/2, and sterol regulatory element-binding protein (SREBP). Maprotiline and phenylephrine induced binding of SREBP-2 to sterol regulatory element (SRE) region on the iPLA2 promoter, as determined by electrophoretic mobility shift assay (EMSA). Together, results indicate that stimulation of adrenoreceptors causes increased iPLA2 expression via MAP kinase/ERK 1/2 and SREBP, and suggest a possible mechanism for effect of CNS noradrenaline on neural plasticity and crosstalk between sterol and glycerophospholipid mediators, that may play a role in physiological or pathophysiological processes in the brain and other organs.

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Acknowledgments

This study was supported by a grant from the National Medical Research Council of Singapore.

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  1. Department of Anatomy, National University of Singapore, Singapore, 119260, Singapore

    Wee-Siong Chew & Wei-Yi Ong

  2. Neurobiology and Ageing Research Programme, National University of Singapore, Singapore, 119260, Singapore

    Wei-Yi Ong

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Chew, WS., Ong, WY. Regulation of Calcium-Independent Phospholipase A2 Expression by Adrenoceptors and Sterol Regulatory Element Binding Protein—Potential Crosstalk Between Sterol and Glycerophospholipid Mediators. Mol Neurobiol 53, 500–517 (2016). https://doi.org/10.1007/s12035-014-9026-9

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