Noradrenergic Depression of Neuronal Excitability in the Entorhinal Cortex via Activation of TREK-2K(+) Channels

Department of Pharmacology, Physiology and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota 58203.
Journal of Biological Chemistry (Impact Factor: 4.57). 03/2009; 284(16):10980-91. DOI: 10.1074/jbc.M806760200
Source: PubMed


The entorhinal cortex is closely associated with the consolidation and recall of memories, Alzheimer disease, schizophrenia,
and temporal lobe epilepsy. Norepinephrine is a neurotransmitter that plays a significant role in these physiological functions
and neurological diseases. Whereas the entorhinal cortex receives profuse noradrenergic innervations from the locus coeruleus
of the pons and expresses high densities of adrenergic receptors, the function of norepinephrine in the entorhinal cortex
is still elusive. Accordingly, we examined the effects of norepinephrine on neuronal excitability in the entorhinal cortex
and explored the underlying cellular and molecular mechanisms. Application of norepinephrine-generated hyperpolarization and
decreased the excitability of the neurons in the superficial layers with no effects on neuronal excitability in the deep layers
of the entorhinal cortex. Norepinephrine-induced hyperpolarization was mediated by α2A adrenergic receptors and required the functions of Gαi proteins, adenylyl cyclase, and protein kinase A. Norepinephrine-mediated depression on neuronal excitability was mediated
by activation of TREK-2, a type of two-pore domain K+ channel, and mutation of the protein kinase A phosphorylation site on TREK-2 channels annulled the effects of norepinephrine.
Our results indicate a novel action mode in which norepinephrine depresses neuronal excitability in the entorhinal cortex
by disinhibiting protein kinase A-mediated tonic inhibition of TREK-2 channels.

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Available from: Panyue Deng, Aug 06, 2015
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    • "We first examined the expression of CRF and CRF receptors in the EC of rats using immunocytochemistry and western blot. The anatomical location of the EC and the divisions of individual layers in slice of rats were described previously [39], [45]. Strong immunoreactivities for CRF (Fig. 1A, upper panel) and CRF2 (Fig. 1C, upper panel) were detected in the EC whereas there was no detectable immunoreactivity for CRF1 in the EC (Fig. 1B, upper panel). "
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    ABSTRACT: Whereas corticotropin-releasing factor (CRF) has been considered as the most potent epileptogenic neuropeptide in the brain, its action site and underlying mechanisms in epilepsy have not been determined. Here, we found that the entorhinal cortex (EC) expresses high level of CRF and CRF2 receptors without expression of CRF1 receptors. Bath application of CRF concentration-dependently increased the frequency of picrotoxin (PTX)-induced epileptiform activity recorded from layer III of the EC in entorhinal slices although CRF alone did not elicit epileptiform activity. CRF facilitated the induction of epileptiform activity in the presence of subthreshold concentration of PTX which normally would not elicit epileptiform activity. Bath application of the inhibitor for CRF-binding proteins, CRF6-33, also increased the frequency of PTX-induced epileptiform activity suggesting that endogenously released CRF is involved in epileptogenesis. CRF-induced facilitation of epileptiform activity was mediated via CRF2 receptors because pharmacological antagonism and knockout of CRF2 receptors blocked the facilitatory effects of CRF on epileptiform activity. Application of the adenylyl cyclase (AC) inhibitors blocked CRF-induced facilitation of epileptiform activity and elevation of intracellular cyclic AMP (cAMP) level by application of the AC activators or phosphodiesterase inhibitor increased the frequency of PTX-induced epileptiform activity, demonstrating that CRF-induced increases in epileptiform activity are mediated by an increase in intracellular cAMP. However, application of selective protein kinase A (PKA) inhibitors reduced, not completely blocked CRF-induced enhancement of epileptiform activity suggesting that PKA is only partially required. Our results provide a novel cellular and molecular mechanism whereby CRF modulates epilepsy.
    Full-text · Article · Feb 2014 · PLoS ONE
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    • "Horizontal brain slices (400 mm) including the EC, subiculum and hippocampus were cut using a vibrating blade microtome (VT1000S; Leica, Wetzlar, Germany) from 13-to 20- day-old Sprague Dawley rats as described previously (Deng and Lei, 2006; Deng and Lei, 2007; Lei et al., 2007; Xiao et al., 2009a; Wang et al., 2012). After being deeply anesthetized with isoflurane, rats were decapitated and their brains were dissected out in ice-cold saline solution that contained (in mM) "
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    ABSTRACT: Bombesin and the bombesin-like peptides including neuromedin B (NMB) and gastrin-releasing peptide (GRP) are important neuromodulators in the brain. We studied their effects on GABAergic transmission and epileptiform activity in the entorhinal cortex (EC). Bath application of bombesin concentration-dependently increased both the frequency and amplitude of sIPSCs recorded from the principal neurons in the EC. Application of NMB and GRP exerted the same effects as bombesin. Bombesin had no effects on mIPSCs recorded in the presence of TTX but slightly depressed the evoked IPSCs. Omission of extracellular Ca(2+) or inclusion of voltage-gated Ca(2+) channel blockers, Cd(2+) and Ni(2+) , blocked bombesin-induced increases in sIPSCs suggesting that bombesin increases GABA release via facilitating extracellular Ca(2+) influx. Bombesin induced membrane depolarization and slightly increased the input resistance of GABAergic interneurons recorded from layer III of the EC. The action potential firing frequency of the interneurons was also increased by bombesin. Bombesin-mediated depolarization of interneurons was unlikely to be mediated by the opening of a cationic conductance but due to the inhibition of inward rectifier K(+) channels. Bath application of bombesin, NMB and GRP depressed the frequency of the epileptiform activity elicited by deprivation of Mg(2+) from the extracellular solution suggesting that bombesin and the bombesin-like peptides have antiepileptic effects in the brain. © 2013 Wiley Periodicals, Inc.
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    • "Whole-cell patch-clamp recordings using an Axopatch 200B or two Multiclamp 700B amplifiers in voltage-clamp mode from in vitro entorhinal slices were used for experiments. Layer III pyramidal neurons in the medial EC were visually identified with infrared video microscopy and differential interference contrast optics [41], [42], [43], [44]. Recording electrodes were filled with the solution containing (in mM) 100 Cs-gluconate, 0.6 EGTA, 5 MgCl2, 8 NaCl, 2 ATP2Na, 0.3 GTPNa, 40 HEPES and 1 QX-314 (pH 7.3). "
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    ABSTRACT: Adenosine is an inhibitory neuromodulator that exerts antiepileptic effects in the brain and the entorhinal cortex (EC) is an essential structure involved in temporal lobe epilepsy. Whereas microinjection of adenosine into the EC has been shown to exert powerful antiepileptic effects, the underlying cellular and molecular mechanisms in the EC have not been determined yet. We tested the hypothesis that adenosine-mediated modulation of synaptic transmission contributes to its antiepileptic effects in the EC. Our results demonstrate that adenosine reversibly inhibited glutamatergic transmission via activation of adenosine A1 receptors without effects on GABAergic transmission in layer III pyramidal neurons in the EC. Adenosine-induced depression of glutamatergic transmission was mediated by inhibiting presynaptic glutamate release probability and decreasing the number of readily releasable vesicles. Bath application of adenosine also reduced the frequency of the miniature EPSCs recorded in the presence of TTX suggesting that adenosine may interact with the exocytosis processes downstream of Ca(2+) influx. Both Gαi/o proteins and the protein kinase A pathway were required for adenosine-induced depression of glutamatergic transmission. We further showed that bath application of picrotoxin to the EC slices induced stable epileptiform activity and bath application of adenosine dose-dependently inhibited the epileptiform activity in this seizure model. Adenosine-mediated depression of epileptiform activity was mediated by activation of adenosine A1 receptors and required the functions of Gαi/o proteins and protein kinase A pathway. Our results suggest that the depression of glutamatergic transmission induced by adenosine contributes to its antiepileptic effects in the EC.
    Full-text · Article · Apr 2013 · PLoS ONE
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