Acta Physiologica 2011; Volume 203, Supplement 686
Joint Congress of FEPS and Turkish Society of Physiological Sciences
INSULIN INDUCES GABA-A CHANNELS THAT GENERATE TONIC CURRENTS
Abstract number: PC093
Birnir1 Bryndis, Jin1 Zhe, Jin1 Yang, Kumar Mendu1 Suresh, Degerman2 Eva, Groop2 Leif
1Department of Neuroscience, Uppsala University, Uppsala, Sweden
2Lund University Diabetic Center, Lund University, Lund, Sweden
The objective was to examine effects of metabolic hormones on neuronal excitability with the inital focus on insulin. Insulin signaling to the brain is important not only for metabolic homeostasis but also for higher brain functions such as cognition.
We used the patch-clamp whole-cell and single-channel recordings to examine the neuronal excitability.
GABA (g-aminobutyric acid) decreases neuronal excitability by activating GABA-A channels that generate phasic and tonic currents. The level of tonic inhibition in neurons varies. Here we show in acute rat hippocamal slices that 1 nM insulin "turns on" new extrasynaptic GABA-A channels in CA1 pyramidal neurons resulting in decreased frequency of action potential firing (1). The channels are activated by more than million times lower GABA concentrations than synaptic channels, generate tonic currents and show outward rectification. The single-channel current amplitude is related to the GABA concentration resulting in a single-channel GABA affinity (EC50) in intact CA1 neurons of 17 pM with the maximal current amplitude reached with 1 nM GABA. They are inhibited by GABA-A antagonists but have novel pharmacology as the benzodiazepine flumazenil and zolpidem are inverse agonists.
The results show that tonic rather than synaptic conductances regulate basal neuronal excitability when significant tonic conductance is expressed and demonstrate an unexpected hormonal control of the inhibitory channel subtypes and excitability of hippocampal neurons. The insulin-induced new channels provide a specific target for rescuing cognition in health and in diseases like diabetes, dementia and Alzheimer disease.
Reference: 1) Jin et al. (2011) PLOS One 6: e16188.
To cite this abstract, please use the following information:
Acta Physiologica 2011; Volume 203, Supplement 686 :PC093