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

Neurobiol Dis. 2014 Oct;70:74-89. doi: 10.1016/j.nbd.2014.06.004. Epub 2014 Jun 19.

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.

Keywords: AMPA; EP1; EP2; GluK2; GluK4; GluK5; Kainate receptor; Protein Kinase C; Status epilepticus.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cells, Cultured
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuroimmunomodulation / physiology
  • Oocytes / physiology
  • Protein Kinase C / metabolism*
  • Rats, Sprague-Dawley
  • Receptors, Kainic Acid / metabolism*
  • Receptors, Prostaglandin E, EP1 Subtype / genetics
  • Receptors, Prostaglandin E, EP1 Subtype / metabolism*
  • Seizures / physiopathology
  • Signal Transduction
  • Status Epilepticus / pathology
  • Status Epilepticus / physiopathology*
  • Xenopus

Substances

  • Gluk1 kainate receptor
  • Ptger1 protein, mouse
  • Ptger1 protein, rat
  • Receptors, Kainic Acid
  • Receptors, Prostaglandin E, EP1 Subtype
  • Protein Kinase C