A switch in G protein coupling for type 1 corticotropin-releasing factor receptors promotes excitability in epileptic brains.
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.
Molecular Medicine Research Group, Robarts Research Institute, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 5K8, Canada. Department of Physiology and Pharmacology, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 3K7, Canada.
Chakravarthi
C
Narla
Molecular Medicine Research Group, Robarts Research Institute, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 5K8, Canada. Department of Physiology and Pharmacology, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 3K7, Canada.
Tanner
T
Scidmore
Molecular Medicine Research Group, Robarts Research Institute, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 5K8, Canada. Graduate Program in Neuroscience, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 5K8, Canada.
Jaymin
J
Jeong
Molecular Medicine Research Group, Robarts Research Institute, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 5K8, Canada.
Michelle
M
Everest
Department of Physiology and Pharmacology, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 3K7, Canada. Department of Biology, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 3K7, Canada.
Peter
P
Chidiac
Molecular Medicine Research Group, Robarts Research Institute, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 5K8, Canada. Department of Physiology and Pharmacology, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 3K7, Canada. Graduate Program in Neuroscience, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 5K8, Canada. mpoulter@robarts.ca.
Michael O
MO
Poulter
D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism*; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D066195:Piriform Cortex / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000099052:CRF Receptor, Type 1
D044385:GTP-Binding Protein alpha Subunits; D020710:RGS Proteins; C514563:RGS2 protein, rat; D018019:Receptors, Corticotropin-Releasing Hormone; C105345:Rgs2 protein, mouse; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone