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Differential effects of Go and Gi2 on seizure threshold
Author(s) -
Kehrl Jason,
Stern Matt,
Charbeneau Raelene,
Neubig Richard
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1010.2
Subject(s) - pentylenetetrazol , inhibitory postsynaptic potential , bicuculline , antagonist , chemistry , epilepsy , g protein , pharmacology , kindling , protein subunit , seizure threshold , microbiology and biotechnology , neuroscience , receptor , signal transduction , endocrinology , biology , anticonvulsant , biochemistry , gene
The inhibitory G protein family, G i/o , play important roles in neuronal excitability and epileptic pathways. The G i/o family may protect from seizures by inhibiting neurotransmitter release via inhibition of N‐type calcium channels and activation ofhyperpolerizing potassium channels. However, increased activation of the G i/o ‐coupled GABA B receptor produces absence seizures. The G i/o family member responsible for each of these physiological effects has not been established. We aim to understand the role of G o and G i2 , two G i/o family members, in altering seizure thresholds. We utilize mouse models with enhanced signaling through G i2 and G o due to a genomic knock‐in (G184S) within the α subunit that prevents negative regulation by the Regulators of G protein Signaling. Mice with enhanced G i2 signaling, but not G o , show reduced seizure severity and death after administration of the competitive GABA A antagonist bicuculline. In a kindling model with repeated injections of subthreshold doses of pentylenetetrazol (35mg/kg) G o G184S mice, but not G i2 G184S mice, show a more rapid onset of tonic‐clonic seizures and/or death. Together these data indicate opposing roles for these inhibitory G proteins in setting the murine seizure threshold. Supported by RO1‐GM39561 (RRN) and 5T32GM008322 (JMK)