Different effects of ω-conotoxin GVIA at excitatory and inhibitory synapses in rat CA1 hippocampal neurons

doi:10.1016/0006-8993(93)90214-8

Brain Research

Volume 616, Issues 1–2, 9 July 1993, Pages 236-241

https://doi.org/10.1016/0006-8993(93)90214-8 Get rights and content

Abstract

The nature of the coupling mechanism of presynaptic calcium channels involved in the release of neurotransmitters in the mammalian central nervous system is unknown. Using intracellular recordings from CA1 neurons in the rat hippocampal slice preparation, we show that the N-type calcium channels antagonist omega-conotoxin GVIA (ω-CgTx) blocks partially the excitatory (EPSP) and totally the inhibitory (IPSP) synaptic transmission in CA1 hippocampal pyramidal neurons. In addition, the inhibitory effect of ω-CgTx on IPSPs is strongly depressed by intrahippocampal injection of PTX, while the effect on EPSP is not. The results suggest that the nature or the regulation of calcium channels might be different, depending on the location of these channels on excitatory or inhibitory terminals.

Reference (32)

BernathS.
Calcium-independent release of amino-acid neurotransmitters: fact or artifact?
Prog. Neurobiol.
(1992)
CaseyP.J. et al.
G-protein involvement in receptor-effector coupling
J. Biol. Chem.
(1988)
DutarP. et al.
ω-Conotoxin GVIA blocks synaptic transmission in the CA1 field of the hippocampus
Eur. J. Pharmacol.
(1989)
EwaldD.A. et al.
Differential G-protein-mediated coupling of neurotransmitter receptors to Ca²⁺ channels in rat dorsal root ganglion neurons in vitro
Neuron
(1989)
KamiyaH. et al.
Synthetic ω-conotoxin blocks synaptic transmission in the hippocampus in vitro
Neurosci. Lett.
(1988)
MurayamaT. et al.
Loss of the inhibitory function of the guanine nucleotide regulatory component of adenylate cyclase due to its ADP ribosylation by islet-activating protein, pertussis toxin, in adipocyte membrane
J. Biol. Chem.
(1983)
PotierB. et al.
Presynaptic inhibitory effect of baclofen on hippocampal inhibitory synaptic transmission involves a pertussis toxin-sensitive G-protein
Eur. J. Pharmacol.
(1993)
RijnhoutI. et al.
Failure of ω-conotoxin to block L-channels associated with [3H]5-HT release in rat brain slices
Neurosci. Lett.
(1990)
ScottR.H. et al.
The agonist effect of Bay K 8644 on neuronal calcium channel currents is promoted by G-protein activation
Neurosci. Lett.
(1988)
SherE. et al.
ω-Conotoxin-sensitive voltage-operated calcium channels in vertebrate cells
Neuroscience
(1991)

SongS-Y. et al.

Different GTP-binding proteins mediate regulation of calcium channels by acetylcholine and noradrenaline in rat sympathetic neurons

Brain Res.

(1989)

ToselliM. et al.

Pharmacological characterization of voltage-dependent calcium currents in rat hippocampal neurons

Neurosci. Lett.

(1990)

Van der PloegI. et al.

Limited distribution of pertussis toxin in rat brain after injection into the lateral cerebral ventricles

Neuroscience

(1991)

AndradeR. et al.

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

Science

(1986)

BergamaschiS. et al.

Modulation of dihydropyridine-sensitive calcium channels: a role for G proteins

Eur. Neurol.

(1990)

DolphinA.

G protein modulation of calcium currents in neurons

Annu. Rev. Physiol.

(1990)

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Different effects of ω-conotoxin GVIA at excitatory and inhibitory synapses in rat CA1 hippocampal neurons

Abstract

Prog. Neurobiol.

J. Biol. Chem.

Eur. J. Pharmacol.

Neuron

Neurosci. Lett.

J. Biol. Chem.

Eur. J. Pharmacol.

Neurosci. Lett.

Neurosci. Lett.

Neuroscience

Brain Res.

Neurosci. Lett.

Neuroscience

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

Science

Modulation of dihydropyridine-sensitive calcium channels: a role for G proteins

Eur. Neurol.

G protein modulation of calcium currents in neurons

Annu. Rev. Physiol.

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