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Failure of omega-conotoxin to block L-channels associated with [3H]5-HT release in rat brain slices
I Rijnhout1, D R Hill, D N Middlemiss
1Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, U.K.
Abstract:
The effects of the mixed N- and L-type voltage-sensitive calcium channel (VSCC) antagonist, omega-conotoxin GVIA and the L-type VSCC agonist Bay K-8644 on calcium-dependent, potassium evoked release of [3H]5-hydroxtryptamine ([3H]5-HT) were investigated in slices of rat hippocampus. Bay K-8644 (1 microM) enhanced, whilst omega-conotoxin (10-30 nM) attenuated, but did not abolish, evoked release of [3H]5-HT. The facilitatory actions of Bay K-8644 on evoked release were unaffected by concentrations of omega conotoxin that significantly inhibited [3H]5-HT release. The experiments indicate that concentrations of omega-conotoxin which inhibit neurotransmitter release by blockade of N-type VSCC, may leave L-type calcium channel activity unaffected.
Insights
Omega-conotoxin GVIA, an N- and L-type voltage-sensitive calcium channel (VSCC) antagonist, partially inhibited [3H]5-HT release in rat hippocampus. Bay K-8644, an L-type VSCC agonist, enhanced release, with effects unaffected by omega-conotoxin.
Area of Science:
- Neuroscience
- Pharmacology
- Neurotransmitter Release
Background:
- Voltage-sensitive calcium channels (VSCCs) play a crucial role in neurotransmitter release.
- N- and L-type VSCCs are implicated in regulating serotonin ([3H]5-HT) release in the hippocampus.
- Understanding the specific roles of different VSCC subtypes is essential for developing targeted therapeutics.
Purpose of the Study:
- To investigate the distinct roles of N- and L-type VSCCs in regulating potassium-evoked [3H]5-HT release in rat hippocampus.
- To determine the effects of omega-conotoxin GVIA (N- and L-type VSCC antagonist) and Bay K-8644 (L-type VSCC agonist) on [3H]5-HT release.
Main Methods:
- Experiments were conducted using rat hippocampal slices.
- Potassium-evoked release of [3H]5-HT was measured.
- The effects of omega-conotoxin GVIA and Bay K-8644 at specific concentrations were analyzed.
Main Results:
- Bay K-8644 (1 microM) significantly enhanced evoked [3H]5-HT release.
- Omega-conotoxin GVIA (10-30 nM) attenuated, but did not abolish, evoked [3H]5-HT release.
- The facilitatory effect of Bay K-8644 was not affected by omega-conotoxin concentrations that inhibited [3H]5-HT release.
Conclusions:
- N-type VSCC blockade by omega-conotoxin does not fully inhibit L-type calcium channel activity involved in [3H]5-HT release.
- Distinct contributions of N- and L-type VSCCs to serotonin release in the hippocampus were demonstrated.
- These findings suggest differential modulation of neurotransmitter release by specific VSCC subtypes.