GABAB Receptor Activation Inhibits Neuronal Excitability and Spatial Learning in the Entorhinal Cortex by Activating TREK-2 K+ Channels

Deng, Pan; Xiao, Zhaoyang; Yang, Chuanxiu; Rojanathammanee, Lalida; Grisanti, Laurel A.; Watt, John A.; Geiger, Jonathan D.; Liu, Rugao; Porter, James E.; Lei, Saobo

doi:10.1016/j.neuron.2009.06.022

Cited by 109 publications

(105 citation statements)

References 67 publications

(110 reference statements)

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“…Our results show that both bath and local somatic application of baclofen lead to hyperpolarization and a decrease in somatic input resistance in layer 5 pyramidal neurons. This effect is similar to that observed previously at the soma of neurons in other cortical areas and brain regions (Benardo 1994;Deng et al 2009;Gähwiler and Brown 1985;Lüscher et al 1997;Newberry and Nicoll 1985). Furthermore, we show that bath application of baclofen decreases neuronal excitability, as observed by a rightward shift of the input-output relationship (Fig.…”

Section: Discussionsupporting

confidence: 92%

“…5). Similar results have been reported in neurons from the entorhinal cortex (Deng et al 2009). These effects of GABA B receptors are likely to be due to activation of a potassium conductance, as they were occluded by low concentrations of barium.…”

Section: Discussionsupporting

confidence: 89%

“…This slow inhibition is thought to be mediated via activation of G-protein-coupled inwardly rectifying potassium (GIRK) channels belonging to the Kir3 potassium channel family (Chen and Johnston 2005;Gähwiler and Brown 1985;Lüscher et al 1997;Newberry and Nicoll 1985). In addition, it has been shown recently that postsynaptic GABA B receptors can activate TREK-2 channels, a two pore-domain potassium channel (Deng et al 2009). By increasing membrane permeability to potassium, GABA B receptors play a crucial role in regulating neuronal excitability via hyperpolarizing the resting membrane potential and reducing the input resistance (Gähwiler and Brown 1985;Lüscher et al 1997).…”

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confidence: 99%

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Somatic and dendritic GABA_B receptors regulate neuronal excitability via different mechanisms

Breton

Stuart

2012

Journal of Neurophysiology

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Breton J-D, Stuart GJ. Somatic and dendritic GABA B receptors regulate neuronal excitability via different mechanisms. J Neurophysiol 108: 2810 -2818, 2012. First published September 5, 2012 doi:10.1152/jn.00524.2012.-GABA B receptors play a key role in regulating neuronal excitability in the brain. Whereas the impact of somatic GABA B receptors on neuronal excitability has been studied in some detail, much less is known about the role of dendritic GABA B receptors. Here, we investigate the impact of GABA B receptor activation on the somato-dendritic excitability of layer 5 pyramidal neurons in the rat barrel cortex. Activation of GABA B receptors led to hyperpolarization and a decrease in membrane resistance that was greatest at somatic and proximal dendritic locations. These effects were occluded by low concentrations of barium (100 M), suggesting that they are mediated by potassium channels. In contrast, activation of dendritic GABA B receptors decreased the width of backpropagating action potential (APs) and abolished dendritic calcium electrogenesis, indicating that dendritic GABA B receptors regulate excitability, primarily via inhibition of voltage-dependent calcium channels. These distinct actions of somatic and dendritic GABA B receptors regulated neuronal output in different ways. Activation of somatic GABA B receptors led to a reduction in neuronal output, primarily by increasing the AP rheobase, whereas activation of dendritic GABA B receptors blocked burst firing, decreasing AP output in the absence of a significant change in somatic membrane properties. Taken together, our results show that GABA B receptors regulate somatic and dendritic excitability of cortical pyramidal neurons via different cellular mechanisms. Somatic GABA B receptors activate potassium channels, leading primarily to a subtractive or shunting form of inhibition, whereas dendritic GABA B receptors inhibit dendritic calcium electrogenesis, leading to a reduction in bursting firing.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 89%

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confidence: 99%

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Somatic and dendritic GABA_B receptors regulate neuronal excitability via different mechanisms

Breton

Stuart

2012

Journal of Neurophysiology

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“…40 AF-associated APD shortening has previously been attributed to increased I K1 current, downregulation of I Ca,L , and constitutively active I K,ACh (despite decreased K ir 3.1 and K ir 3.4 subunits underlying the current). 2,41,42 In the present cAF cohort, APD abbreviation was linked to increased K ir 2.1 and KCNQ1 channel expression, in addition to K 2P 3.1 upregulation. Expression of the L-type calcium channel α subunit Ca v 1.2 was not significantly altered, suggesting that the reduction of I Ca,L is not caused primarily by downregulation of the expression of its α subunit.…”

Section: Apd Shortening In Caf Patients: Significance Of K 2p 31 Andmentioning

confidence: 58%

Upregulation of K _2P 3.1 K ⁺ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation

et al. 2015

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Background-Antiarrhythmic management of atrial fibrillation (AF) remains a major clinical challenge. Mechanismbased approaches to AF therapy are sought to increase effectiveness and to provide individualized patient care. K 2P 3.1 (TASK-1 [tandem of P domains in a weak inward-rectifying K + channel-related acid-sensitive K + channel-1]) 2-poredomain K + (K 2P ) channels have been implicated in action potential regulation in animal models. However, their role in the pathophysiology and treatment of paroxysmal and chronic patients with AF is unknown. Methods and Results-Right and left atrial tissue was obtained from patients with paroxysmal or chronic AF and from control subjects in sinus rhythm. Ion channel expression was analyzed by quantitative real-time polymerase chain reaction and Western blot. Membrane currents and action potentials were recorded using voltage-and current-clamp techniques. K 2P 3.1 subunits exhibited predominantly atrial expression, and atrial K 2P 3.1 transcript levels were highest among functional K 2P channels. K 2P 3.1 mRNA and protein levels were increased in chronic AF. Enhancement of corresponding currents in the right atrium resulted in shortened action potential duration at 90% of repolarization (APD 90 ) compared with patients in sinus rhythm. In contrast, K 2P 3.1 expression was not significantly affected in subjects with paroxysmal AF. Pharmacological K 2P 3.1 inhibition prolonged APD 90 in atrial myocytes from patients with chronic AF to values observed among control subjects in sinus rhythm. Conclusions-Enhancement of atrium-selective K 2P 3.1 currents contributes to APD shortening in patients with chronic AF, and K 2P 3.1 channel inhibition reverses AF-related APD shortening. These results highlight the potential of K 2P 3.1 as a novel drug target for mechanism-based AF therapy.

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“…Negative controls were obtained, treating cultured neurons identically without adding the primary antibody, and no neuronal labeling was observed. The same antibodies against TREK-1 and TREK-2 were carefully tested by Deng et al (2009), and all of them have been successfully used in trigeminal ganglion cells recently (Yamamoto et al, 2009). All antibodies were purchased from Santa Cruz Biotechnology, and all antibody solutions were prepared in 2% NDS in PBS.…”

Section: Introductionmentioning

confidence: 99%

Activation of TREK Currents by the Neuroprotective Agent Riluzole in Mouse Sympathetic Neurons

Cadaveira-Mosquera¹,

Ribeiro²,

Reboreda³

et al. 2011

J. Neurosci.

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ϩ channel) mRNA, and the expression of these three proteins was confirmed by immunocytochemistry in mSCG neurons. I RIL was enhanced by zinc, inhibited by barium and fluoxetine, but unaffected by quinine and ruthenium red, strongly suggesting that it was carried through TREK-1/2 channels. Consistently, a channel with properties identical with the heterologously expressed TREK-2 was recorded in most (75%) cell-attached patches. These results provide the first evidence for the expression of K2P channels in the mammalian autonomic nervous system, and they extend the impact of these channels to the entire nervous system.

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GABAB Receptor Activation Inhibits Neuronal Excitability and Spatial Learning in the Entorhinal Cortex by Activating TREK-2 K+ Channels

Cited by 109 publications

References 67 publications

Somatic and dendritic GABA_B receptors regulate neuronal excitability via different mechanisms

Somatic and dendritic GABA_B receptors regulate neuronal excitability via different mechanisms

Upregulation of K _2P 3.1 K ⁺ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation

Activation of TREK Currents by the Neuroprotective Agent Riluzole in Mouse Sympathetic Neurons

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GABAB Receptor Activation Inhibits Neuronal Excitability and Spatial Learning in the Entorhinal Cortex by Activating TREK-2 K+ Channels

Cited by 109 publications

References 67 publications

Somatic and dendritic GABAB receptors regulate neuronal excitability via different mechanisms

Somatic and dendritic GABAB receptors regulate neuronal excitability via different mechanisms

Upregulation of K 2P 3.1 K + Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation

Activation of TREK Currents by the Neuroprotective Agent Riluzole in Mouse Sympathetic Neurons

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Somatic and dendritic GABA_B receptors regulate neuronal excitability via different mechanisms

Somatic and dendritic GABA_B receptors regulate neuronal excitability via different mechanisms

Upregulation of K _2P 3.1 K ⁺ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation