GABAB agonists modulate a transient potassium current in cultured mammalian hippocampal neurons

doi:10.1016/0304-3940(90)90236-3

Neuroscience Letters

Volume 118, Issue 1, 2 October 1990, Pages 9-13

https://doi.org/10.1016/0304-3940(90)90236-3 Get rights and content

Abstract

Depolarization of voltage-clamped cultured rat hippocampal neurons from holding potentials more negative than −60 mV produced a transient outward current with the characteristics of an A-current: it was 50% inactivated at a holding potential of −85 mV and blocked by 4-aminopyridine (1 mM). In the presence of GABA or baclofen (50–200 μM), with or without bicuculline, inactivation of this current was shifted to more positive potentials so that there was little inactivation at −70 mV. Activation of the A-current was also shifted to more positive potentials by these agonists, but the voltage dependence of activation of the sodium current was unaffected. If A-currents with similar properties can influence the time course of action potentials in presynaptic terminals, GABA_B agonists could make action potentials briefer by potentiating the A-current and hence depress transmitter release.

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Citation Excerpt :
In addition, it has been shown that GABAB receptor activation increase the energy barrier for vesicle fusion in a Gαi/o-dependent manner (Rost et al., 2011). Furthermore, GABAB receptors can activate presynaptic inwardly rectifying K+ channels, which also contribute to the inhibition of transmitter release (Fernandez-Alacid et al., 2009; Ladera et al., 2008; Saint, Thomas, & Gage, 1990). Postsynaptic GABAB receptors activate inwardly rectifying K+ channels (Kir3.1–3.4 also known as GIRK1–4) via Gβγ thereby generating slow and prolonged inhibitory postsynaptic potentials hyperpolarizing the membrane (Andrade, Malenka, & Nicoll, 1986; Luscher, Jan, Stoffel, Malenka, & Nicoll, 1997).
γ-Amino butyric acid (GABA_B) receptors are heterodimeric G protein-coupled receptors expressed throughout the central nervous system in virtually all neurons. They control the excitability of neurons via activation of different downstream effector systems in pre- and postsynaptic neurons and as such regulate all major brain functions including synaptic plasticity, neuronal network activity, and neuronal development. Accordingly, GABA_B receptors have been implicated in a variety of neurological disorders and thus are regarded as promising drug targets. A key factor determining the extent of GABA_B receptor-mediated inhibition is the level of receptors at the cell surface available for signaling. There is increasing evidence that cell surface expression of functional GABA_B receptors is affected in neurological diseases. This diminishes inhibitory control of neuronal excitation and may contribute to the disease state. Here, we discuss recent findings on mechanisms involved in regulating cell surface expression of GABA_B receptors in addiction, neuropathic pain, and brain ischemia.
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The primary function of neurons is to integrate synaptic inputs and to transmit the results to other cells. Recent studies with somatic whole-cell recordings have shown that separate excitatory inputs to hippocampal or cortical pyramidal neurons are summated non-linearly. In the present study, we examined how postsynaptic potentials (PSPs) are summated along the dendrites employing fast optical voltage imaging techniques. Rat hippocampal slices were stained with a fluorescent voltage-sensitive dye (JPW1114) and optical signals were monitored with a 16×16 photodiode array system. Two independent input pathways were stimulated individually or in pairs through glass electrodes such that different locations of the dendrites received separate synaptic inputs. We found that (1) the summation of PSPs was sub-linear along the entirety of dendrites, (2) the blockade of GABA_A receptors suppressed sub-linearity and (3) further blockade of GABA_B receptors suppressed sub-linearity of the summation of separate inputs on apical dendrites.
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Whole-cell patch-clamp recordings were obtained from nodose ganglion neurons acutely dissociated from 10–30-day-old rats to characterize the Ca²⁺ channel types that are modulated by GABA_B and μ-opioid receptors. Five components of high-threshold current were distinguished on the basis of their sensitivity to blockade by ω-conotoxin GVIA, nifedipine, ω-agatoxin IVA and ω-conotoxin MVIIC. Administration of the μ-opioid agonist H-Tyr-D-Ala-Gly-Phe(N-Me)-Gly-ol (0.3–1 mM) or the GABA_B agonist baclofen in saturating concentrations suppressed high-threshold Ca²⁺ currents by 49.9±2.4% n=69) and 18.7±2.1% n=35), respectively. The inhibition by H-Tyr-D-Ala-Gly-Phe(N-Me)-Gly-ol exceeded that by baclofen in virtually all neurons that responded to both agonists (67%), and occlusion experiments revealed that responses to μ-opioid and GABA_B receptor activation were not linearly additive. In addition, administration of staurosporine, a non-selective inhibitor of protein kinase A and C, did not affect the inhibitory responses to either agonist or prevent the occlusion of baclofen-induced current inhibition by H-Tyr-D-Ala-Gly-Phe(N-Me)-Gly-ol. Blockade of N-type channels by ω-conotoxin GVIA eliminated current suppression by baclofen in all cells tested n=11). μ-Opioid-induced inhibition in current was abolished by ω-conotoxin GVIA in 12 of 30 neurons tested, but was only partially reduced in the remaining 18 neurons. In the latter cells administration of ω-agatoxin IVA reduced, but did not eliminate the μ-opioid sensitive current component that persisted after blockade of N-type channels. This residual component of μ-opioid-sensitive current was blocked completely by ω-conotoxin MVIIC in nine neurons, whereas responses to H-Tyr-D-Ala-Gly-Phe(N-Me)-Gly-ol were still recorded in the remaining cells after administration of these Ca²⁺ channel toxins and nifedipine. Dihydropyridine-sensitive (L-type) current was not affected by activation of μ-opioid or GABA_B receptors in any of the neurons.
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Recent advances in the study of receptor-regulated ion channels include the cloning of the genes encoding three types of potassium channel that are favorite targets of receptors for transmitters and hormones. Studies of these channels have also provided a strong indication that G-protein βγ subunits may gate ion channels via direct protein—protein interactions. Similarities between channel regulation by natriuretic peptides and channel regulation by secreted peptide products of the Alzheimer's β-amyloid precursor protein offer hints for the existence of a receptor for the latter. There are also other novel examples of channel regulation in excitable and nonexcitable cells, including liver cells and blood cells.
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GABAB agonists modulate a transient potassium current in cultured mammalian hippocampal neurons

Abstract

TIPS

Modulation of a transient outward current in serotonergic neurons by α1-adrenoreceptors

Nature (Lond.)

Characteristics of a slow hyperpolarizing synaptic potential in rat hippocampal pyramidal cells in vitro

J. Neurophysiol.

A G protein couples serotonin and GABAB receptors to the same channels in hippocampus

Science

(−) baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor

Nature (Lond.)

Voltage-activated membrane currents in rat cerebellar granule neurones

GABAB-receptor-activated K+ current in voltage-clamped CA3 pyramidal cells in hippocampal cultures

GABAB-receptor mediated inhibition of potassium-evoked release of endogenous 5-hydroxytryptamine from mouse frontal cortex

Br. J. Pharmacol.

A transient outward current in a mammalian central neurone blocked by 4-aminopyridine

Nature (Lond.)

Conductance changes underlying a late synaptic hyperpolarization in hippocampal CA3 neurons

J. Neurophysiol.

Improved patch-clamp techniques for high resolution current recording from cells and cell-free membrane patches

Pflügers Arch.

GABA_B agonists modulate a transient potassium current in cultured mammalian hippocampal neurons

Modulation of a transient outward current in serotonergic neurons by α₁-adrenoreceptors

A G protein couples serotonin and GABA_B receptors to the same channels in hippocampus

GABA_B-receptor-activated K⁺ current in voltage-clamped CA3 pyramidal cells in hippocampal cultures

GABA_B-receptor mediated inhibition of potassium-evoked release of endogenous 5-hydroxytryptamine from mouse frontal cortex