A switch in G protein coupling for type 1 corticotropin-releasing factor receptors promotes excitability in epileptic brains

Sci Signal. 2016 Jun 14;9(432):ra60. doi: 10.1126/scisignal.aad8676.

Abstract

Anxiety and stress increase the frequency of epileptic seizures. These behavioral states induce the secretion of corticotropin-releasing factor (CRF), a 40-amino acid neuropeptide neurotransmitter that coordinates many behavioral responses to stress in the central nervous system. In the piriform cortex, which is one of the most seizurogenic regions of the brain, CRF normally dampens excitability. By contrast, CRF increased the excitability of the piriform cortex in rats subjected to kindling, a model of temporal lobe epilepsy. In nonkindled rats, CRF activates its receptor, a G protein (heterotrimeric guanosine triphosphate-binding protein)-coupled receptor, and signals through a Gαq/11-mediated pathway. After seizure induction, CRF signaling occurred through a pathway involving Gαs This change in signaling was associated with reduced abundance of regulator of G protein signaling protein type 2 (RGS2), which has been reported to inhibit Gαs-dependent signaling. RGS2 knockout mice responded to CRF in a similar manner as epileptic rats. These observations indicate that seizures produce changes in neuronal signaling that can increase seizure occurrence by converting a beneficial stress response into an epileptic trigger.

MeSH terms

  • Animals
  • Corticotropin-Releasing Hormone / genetics
  • Corticotropin-Releasing Hormone / metabolism
  • Epilepsy / genetics
  • Epilepsy / metabolism*
  • GTP-Binding Protein alpha Subunits / genetics
  • GTP-Binding Protein alpha Subunits / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Piriform Cortex / metabolism*
  • Piriform Cortex / pathology
  • Piriform Cortex / physiopathology
  • RGS Proteins / genetics
  • RGS Proteins / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Corticotropin-Releasing Hormone / genetics
  • Receptors, Corticotropin-Releasing Hormone / metabolism*
  • Signal Transduction*

Substances

  • GTP-Binding Protein alpha Subunits
  • RGS Proteins
  • RGS2 protein, rat
  • Receptors, Corticotropin-Releasing Hormone
  • Rgs2 protein, mouse
  • CRF receptor type 1
  • Corticotropin-Releasing Hormone