The prostaglandin EP1 receptor potentiates kainate receptor activation via a protein kinase C pathway and exacerbates status epilepticus

doi:10.1016/j.nbd.2014.06.004

Neurobiology of Disease

Volume 70, October 2014, Pages 74-89

https://doi.org/10.1016/j.nbd.2014.06.004 Get rights and content

Highlights

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Mice lacking EP1 displayed a reduced likelihood to enter status epilepticus.
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EP1 receptor lacking mice had decreased hippocampal neurodegeneration.
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EP1 receptor lacking mice showed a blunted inflammatory response.
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Native and recombinant kainate receptors are potentiated by EP1 activation.
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PKC acting on residues in GluK5 underlie kainate receptor potentiation by EP1.

Abstract

Prostaglandin E2 (PGE2) regulates membrane excitability, synaptic transmission, plasticity, and neuronal survival. The consequences of PGE2 release following seizures has been the subject of much study. Here we demonstrate that the prostaglandin E2 receptor 1 (EP1, or Ptger1) modulates native kainate receptors, a family of ionotropic glutamate receptors widely expressed throughout the central nervous system. Global ablation of the EP1 gene in mice (EP1-KO) had no effect on seizure threshold after kainate injection but reduced the likelihood to enter status epilepticus. EP1-KO mice that did experience typical status epilepticus had reduced hippocampal neurodegeneration and a blunted inflammatory response. Further studies with native prostanoid and kainate receptors in cultured cortical neurons, as well as with recombinant prostanoid and kainate receptors expressed in Xenopus oocytes, demonstrated that EP1 receptor activation potentiates heteromeric but not homomeric kainate receptors via a second messenger cascade involving phospholipase C, calcium and protein kinase C. Three critical GluK5 C-terminal serines underlie the potentiation of the GluK2/GluK5 receptor by EP1 activation. Taken together, these results indicate that EP1 receptor activation during seizures, through a protein kinase C pathway, increases the probability of kainic acid induced status epilepticus, and independently promotes hippocampal neurodegeneration and a broad inflammatory response.

Introduction

PGE2, a major cyclooxygenase 2 product in the mammalian brain, exerts hormone-like properties that modulate many physiological and pathophysiological functions, among them membrane excitability and synaptic transmission in CA1 pyramidal neurons (Chen and Bazan, 2005). However, the pathways and mechanisms involved remain largely unknown. Kainic acid, an excitatory neurotoxin, when injected into rodents at doses ≥ 20 mg/kg induces seizures that can progress into status epilepticus, which in turn eventually causes development of spontaneous recurrent seizures (epilepsy) in the weeks following (Ben-Ari et al., 1979, Hellier et al., 1998). Kainate receptors (KARs) are ionotropic glutamate receptors composed of GluK1 through GluK5 subunits that are located both presynaptically and postsynaptically throughout the CNS and are involved in synaptic plasticity and transmission (Huettner, 2003, Kamiya, 2002, Lerma, 2003, Pinheiro and Mulle, 2006). Recently we demonstrated expression of the high affinity kainate receptor subunits (GluK4 and GluK5) in the CA3 region of the hippocampus (Rojas et al., 2013), which supported a previous report by Darstein et al. (2003). The expression profile of the high affinity kainate receptor subunits is consistent with the localization of kainic acid binding in the hippocampus. Furthermore, the expression profile of GluK5 (one of the high affinity KA subunits) correlates with the neurodegeneration pattern in the hippocampus following kainic acid injection in rodents.

A prominent neuropathology associated with kainic acid induced status epilepticus is hippocampal neurodegeneration. Recent studies have suggested that signaling via the prostaglandin EP1 receptor may affect the fate of neurons following brain injury. For example, EP1 deficient mice show less neuronal injury following transient forebrain ischemia (Shimamura et al., 2013) and cerebral ischemia (Zhen et al., 2012). Pharmacological inhibition of the EP1 receptor with SC51089 reduces neuronal loss and blood–brain barrier disruption following ischemic injury (Fukumoto et al., 2010, Shimamura et al., 2013) suggesting that EP1 activation may promote cell death. Kawano et al. (2006) demonstrated that EP1 gene inactivation reduced brain injury following NMDA induced excitotoxicity, ischemia or oxygen glucose deprivation, suggesting that the presence of EP1 in normal animals contributes to or exacerbates the injury. Each glutamate receptor subtype (NMDA, AMPA and KA) is likely to play a role in the above mentioned brain injury models. Endogenous kainate receptors are regulated by G_αq coupled receptors that are known to modulate excitotoxicity following seizures (Benveniste et al., 2010, Rojas et al., 2013). EP1 is a G_αq-coupled receptor for PGE2, thus we hypothesized that kainate receptors are targeted by EP1 pathways to contribute to the neuropathology that follows status epilepticus. Here we ask the questions: Does genetic inactivation of EP1 alter kainate induced status epilepticus? Do EP1 knockout mice display reduced neurodegeneration or brain inflammation following kainate induced status epilepticus? Is there cross-talk between kainate receptors and prostanoid receptors and if so, what is the mechanism? To address these questions we combined an in vivo rodent model of kainate induced status epilepticus and functional in vitro studies of native and co-expressed recombinant kainate receptors and prostanoid receptors.

Section snippets

Kainic acid injection

All procedures and experiments conformed to the guidelines of the Animal Care and Use Committee of Emory University. Every effort was made to minimize animal suffering. Wildtype (WT) adult male C57BL/6 mice (≥ 20 g) were obtained from Charles Rivers Labs (Wilmington, MA, USA). EP1 knockout mice (EP1-KO) (Ptger1^tm1Dgen; stock number 011638) were purchased from the Mutant Mouse Regional Resources Center (MMRRC) through the Jackson Laboratory. Disruption of the EP1 gene had been produced by targeted

EP1 disruption reduces the probability of entering status epilepticus in kainate-treated mice

The EP1 receptor has been shown to contribute to cellular toxicity and death in rodent models of ischemic stroke and toxin-induced Parkinsonism (Ahmad et al., 2006, Ahmad et al., 2013, Kawano et al., 2006). Hippocampal expression of the EP1 receptor was verified by RT-PCR on RNA extracted from eight untreated wildtype C57BL/6 mice (not shown), consistent with a previous report by Zhu et al. (2005). We optimized a mouse kainic acid induced seizure model to investigate the importance of EP1 on

Discussion

Here we show expression of the EP1 receptor in the hippocampus of mice and the functional influence of the EP1 receptor on kainic acid induced seizures. Mice lacking a functional EP1 receptor gene displayed a lower tendency to enter status epilepticus when injected with high concentrations of kainic acid although they exhibited a similar behavioral seizure threshold compared to their wildtype counterparts, suggesting that EP1 receptor activation increases the probability for entry of mice into

Acknowledgments

This work is supported by NIH RO1 NS036604, U01 NS058158 (RD), P20 NS080185 and T32 DA15040 (AR), and in part by the neuronal imaging core facilities grant P30 NS055077.

Participated in research design: Rojas and Dingledine.

Conducted experiments: Rojas, Gueorguieva, Quan, Lelutiu and Shaw.

Performed data analysis: Rojas, Gueorguieva, Quan and Dingledine.

Wrote or contributed to the writing of the manuscript: Rojas and Dingledine

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The production of PGE2 in astrocytes, which is mediated by TNF-α released from microglia, triggers Ca2+-dependent astrocytic glutamate release (Bezzi et al., 2001), a mechanism which contributes to activation of extrasynaptic NMDA receptors and is implicated in excitotoxicity. PGE2-EP1 receptor signaling enhances kainic acid receptor activation via phospholipase C, Ca2+ mobilization and PKC activation, a signaling which likely underlies EP1 receptor's permissive role in status epilepticus (Rojas et al., 2014a). PGE2- EP2 receptor activation can exert either beneficial or deleterious effects depending on the cell type involved: neuronal EP2 receptors promote neuroprotection via PKA-dependent signaling activation (Jiang and Dingledine, 2013) whereas EP2 receptor activation in glial cells leads to neurodegeneration, involving cAMP–exchange protein activated by cAMP signaling and the subsequent induction of inducible nitric oxide synthase (iNOS), nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, COX-2 and inflammatory cytokines (Jiang and Dingledine, 2013).
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The prostaglandin EP1 receptor potentiates kainate receptor activation via a protein kinase C pathway and exacerbates status epilepticus

Highlights

Abstract

Introduction

Section snippets

Kainic acid injection

EP1 disruption reduces the probability of entering status epilepticus in kainate-treated mice

Discussion

Acknowledgments

Brain Res.

Brain Res.

Neuropharmacology

Exp. Neurol.

Eur. J. Pharmacol.

Epilepsy Res.

Prog. Neurobiol.

Neurosci. Res.

Neuroscience

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

Electroencephalogr. Clin. Neurophysiol.

J. Physiol. Paris

Brain Res.

Neuroscience

Neurosci. Lett.

Neurobiol. Aging

Prostaglandin EP1 receptor contributes to excitotoxicity and focal ischemic brain damage

Toxicol. Sci.

PGE2 EP1 receptor deletion attenuates 6-OHDA-induced Parkinsonism in mice: old switch, new target

Neurotox. Res.

Functional and molecular aspects of renal prostaglandin receptors

J. Am. Soc. Nephrol.

SUMOylation and phosphorylation of GluK2 regulate kainate receptor trafficking and synaptic plasticity

Nat. Neurosci.

Endogenous PGE2 regulates membrane excitability and synaptic transmission in hippocampal CA1 pyramidal neurons

J. Neurophysiol.

Protein tyrosine kinase-mediated potentiation of currents from cloned NMDA receptors

J. Neurochem.

Selectivity of amino acid transmitters acting at N-methyl-d-aspartate and amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors

Mol. Pharmacol.

Distribution of kainate receptor subunits at hippocampal mossy fiber synapses

J. Neurosci.

Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting

J. Clin. Invest.