K+-evoked dopamine release depends on a cytosolic Ca2+ pool regulated by N-type Ca2+ channels

doi:10.1016/0304-3940(92)90001-N

Neuroscience Letters

Volume 145, Issue 2, 12 October 1992, Pages 121-125

https://doi.org/10.1016/0304-3940(92)90001-N Get rights and content

Abstract

Membrane depolarization evoked by 25–40 mM K⁺ elicited an immediate increase of somatic and neuritic [Ca²⁺]_i in cultured dopaminergic neurons as measured by digital fluorescence microscope imaging. The rise of neuritic [Ca²⁺]_i was inhibited by N-type but not L-type Ca²⁺ channel blockers, while the rise of somatic [Ca²⁺]_i was prevented by both L- and N-type Ca²⁺ channel blockers. Similarly, depolarization-induced [³H]dopamine release was selectively attenuated by N-type Ca²⁺ channel blockers. The present results suggest that [³H]dopamine release from mesencephalic neuronal cell cultures relates to a Ca²⁺-dependent mechanism regulated by N-type channels located in the vicinity of the exocytotic sites within neuritic processes.

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In the present study, we investigated the role of voltage-sensitive calcium channels (VSCCs) on the striatal dopamine release induced by the pesticide glyphosate (GLY) using selective VSCC inhibitors. The dopamine levels were measured by in vivo cerebral microdialysis coupled to HPLC-ED. Nicardipine (L-type VSCC antagonist) or ω-conotoxin MVIIC (non-selective P/Q-type antagonist) had no effect on dopamine release induced by 5 mM GLY. In contrast, flunarizine (T-type antagonist) or ω-conotoxin GVIA (neuronal N-type antagonist) significantly reduced GLY-stimulated dopamine release. These results suggest that GLY-induced dopamine release depends on extracellular calcium and its influx through the T- and N-type VSCCs. These findings were corroborated by molecular docking, which allowed us to establish a correlation between the effect of GLY on blocked VSCC with the observed dopamine release. We propose new molecular targets of GLY in the dorsal striatum, which could have important implications for the assessment of pesticide risks in non-target organisms.
Differential recruitment of N-, P- and Q-type voltage-operated calcium channels in striatal dopamine release evoked by 'regular' and 'burst' firing
2000, Brain Research
Citation Excerpt :
Previous studies on dopamine and other transmitters suggest that low-voltage-activated VOCCs (T-type channels) are not involved in neurotransmitter release [30]. L-type channels are predominantly located in the cell bodies of neurones [13] and do not play a role in terminal calcium entry [26] or neurotransmitter release [6,18] where divorced from afferent action potential traffic, as here. The known pharmacology of the R-type channel is limited: it is insensitive to L-, N-, P- and Q-type channel blockers but can be blocked with low concentrations of inorganic nickel [15] that also block T-type channels.
This study used the peptides ω-conotoxin GVIA, ω-agatoxin IVA and ω-conotoxin MVIIC, singly and in combination, to investigate the relative involvement of N-, P- and Q-type voltage-operated calcium channels in the control of striatal dopamine release. Electrically stimulated dopamine release was measured by fast cyclic voltammetry at carbon fibre microelectrodes in rat striatal slices. The contribution of these channel subtypes was compared in dorsolateral and medial neostriatum for ‘regular’ (discrete) and ‘burst’ stimulation modalities. In dorsolateral neostriatum, a role for N-, P- and Q-type channels was demonstrated for discrete stimulations, whilst at least one other unidentified channel was also involved in dopamine release on ‘burst’ stimulations. Similarly, in the medial axis of the neostriatum, N-, P- and Q-type channels were involved in dopamine release for discrete stimulations, and N-, Q- and at least one other channel type for ‘burst’ stimulations. However, blockade of P-type channels had no effect on dopamine release for ‘burst’ stimulations in the medial axis. In both regions and stimulation paradigms, N-type channels played a greater role than P/Q-type channels. In the medial axis of the neostriatum there was a smaller contribution by N- and P-type channels and the unidentified component, but a greater Q-type contribution to DA release. ‘Burst’ stimulations induced a lesser involvement of N- and P-type channels than discrete stimulations, and a greater role of the unidentified component. In summary, this study suggests that there is heterogeneity in the distribution of functional voltage-operated calcium channel subtypes in the neostriatum, and differences in subtype recruitment for different firing patterns.
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Dorsal column axons of the rat spinal cord are partially protected from anoxic injury following blockade of voltage-sensitive Na⁺ channels and the Na^±–Ca²⁺ exchanger. To examine the potential contribution of voltage-gated Ca²⁺ channels to anoxic injury of spinal cord axons, we studied axonal conduction in rat dorsal columns in vitro following a 60-min period of anoxia. Glass microelectrodes were used to record field potentials from the dorsal columns following distal local surface stimulation. Perfusion solutions containing blockers of voltage-gated Ca²⁺ channels were introduced 60 min prior to onset of anoxia and continued until 10 min after reoxygenation. Pharmacological blocking agents which are relatively selective for L- (verapamil, diltiazem, nifedipine) and N- (ω-conotoxin GVIA) type calcium channels were significantly protective against anoxia-induced loss of conduction, as was non-specific block using divalent cations. Other Ca²⁺ channel blockers (neomycin and ω-conotoxin MVIIC) that affect multiple Ca²⁺ channel types were also neuroprotective. Ni²⁺, which preferentially blocks R-type Ca²⁺ channels more than T-type channels, was also protective in a dose-dependent manner. These data suggest that the influx of Ca²⁺, through L-, N- and possibly R-type voltage-gated Ca²⁺ channels, participates in the pathophysiology of the Ca²⁺-mediated injury of spinal cord axons that is triggered by anoxia.
Involvement of N- and P/Q- but not L- or T-type voltage-gated calcium channels in ischaemia-induced striatal dopamine release in vitro
1997, Brain Research
Calcium influx and transmitter efflux are central events in the neuropathological cascade that occurs during and following cerebral ischaemia. This study explored the role of voltage-gated calcium channels (VGCCs) in ischaemia-induced striatal dopamine (DA) release in vitro. Slices (350 μm thickness) of rat neostriatum were superfused (400 ml/h) with an artificial cerebrospinal fluid (aCSF) at 34°C and subjected to episodes of `ischaemia' by reduction of the glucose concentration from 4 to 2 mM and gassing with 95% N₂/5% CO₂. DA release was monitored with fast cyclic voltammetry at implanted carbon fibre microelectrodes. The time to onset, time to peak, rate and magnitude of DA release were measured. Non-selective blockade of VGCCs with a high concentration of Ni²⁺ (2.5 mM), markedly delayed (P<0.01) and slowed (P<0.05) DA release but preferential blockade of T-type VGCCs with a lower concentration (200 μM) had no effect. DA release was also unaffected by selective antagonism of L-type VGCCs with nimodipine and nicardipine (10 μM each). Selective blockade of N-type VGCCs with ω-conotoxin GVIA (100 nM) delayed DA release (P<0.05) but did not affect its rate or magnitude. Blockade of P- and possibly Q-type VGCCs with ω-agatoxin IVA (up to 200 nM) both delayed (P<0.05) and slowed (P<0.05) DA release. Preferential blockade of P- type VGCCs with neomycin (500 μM) also delayed (P<0.05) and slowed (P<0.05) DA release. These findings suggest that N-, P- and possibly Q- but not L- or T-type VGCCs mediate ischaemia-induced DA release. Although it is not possible to say, on the basis of these results, that the effects are directly upon the dopamine terminals, these calcium channels nevertheless constitute promising targets for therapeutic intervention.
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in non-human primates is antagonized by pretreatment with nimodipine at the nigral, but not at the striatal level
1996, Brain Research
The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to induce parkinsonism in man and non-human primates. Hypotheses concerning the mechanism of action of MPTP have been related to the pathogenesis of nigral cell death in Parkinson's disease. For instance, alterations of calcium influxes have been reported to be implicated in both MPTP-induced parkinsonism and Parkinson's disease. Recently, we reported that nimodipine, a blocker of L-type calcium channels, prevents dopaminergic MPTP-induced neurotoxicity in C57B1/6 black mice. The present study extended these rodent findings to the non-human primate model of Parkinson's disease and assessed the effects of nimodipine, continuously applied by pellet for 18 days, on behavioural, biochemical and histological parameters, following systemic application of MPTP in common marmosets (Callithrix jacchus). The experimental design involved five groups of common marmosets and a total of 24 animals. Monkeys assigned to group I (n = 4) received subcutaneously implanted vehicle pellets 7 days prior to subcutaneous saline injections (control). Monkeys of group II (n = 4) were treated with nimodipine pellets (80 mg) and saline injections. Marmosets in group III (n = 8) were treated with vehicle pellets and received 4 times MPTP (MPTP-HCI, 2 mg/kg body weight subcutaneously, separated by an interval of 24 h for a total of 4 days). Monkeys in group IV (n = 4) and V (n = 4) were treated as group-III animals except for the implantation of nimodipine pellets (80 mg and 120 mg, respectively) 7 days prior to toxin exposure. In common marmosets MPTP induced severe parkinsonian symptoms, a pronounced dopamine depletion in the caudate-putamen (more than 99% of control) and a loss of tyrosine hydroxylase immunoreactive cells in the substantia nigra (50% percent of control) 7 days after MPTP-administration. Pretreatment with nimodipine (120 mg pellets) did neither attenuate the behavioural impairments in MPTP-treated animals nor antagonize the striatal neurotoxin-induced dopamine depletion, but almost completely prevented (in a dose-dependent manner) the MPTP-induced decrease of nigral tyrosine hydroxylase immunoreactive cells. These data suggest that application of nimodipine, during the observation period of 7 days, protects against MPTP-induced neurotoxicity in common marmosets at the cellular nigral level, but not at the synaptic striatal level, implicating differential mechanisms of actions of MPTP-induced neurotoxicity at the nigral versus the striatal level.
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To elucidate the psychotropic actions of calcium (Ca) antagonists, we investigated the effect of the voltage-dependent Ca channel antagonists, nifedipine and flunarizine, on phencyclidine (PCP)-induced changes in the monoamine metabolism in the regional brain areas of rats. The results indicate that the administration of nifedipine alone attenuated dopamine (DA) metabolism in the nucleus caudatus putamen while enhancing serotonin (5-HT) metabolism. By contrast, flunarizine increased DA metabolism. PCP significantly increased DA metabolite levels in the prefrontal cortex, the nucleus caudatus putamen, and the amygdala. The PCP-induced increases in DA metabolism in these regions were significantly antagonized by nifedipine, but not by flunarizine. These results indicate that nifedipine attenuates the PCP-induced hyperactivity of the dopaminergic neurons, suggesting antipsychotic properties for this drug.

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K+-evoked dopamine release depends on a cytosolic Ca2+ pool regulated by N-type Ca2+ channels

Abstract

Neuropharmacology

Neuron

Distribution of Ca2+ channels on frog motor nerve terminals revealed by fluorescent ω-conotoxin

J. Neurosci.

Gangliosides normalize distorted single-cell intracellular free Ca2+ dynamics after toxic doses of glutamate in cerebellar granule cells

Quantal analysis of inhibitory synaptic transmission in the dentate gyrus of rat hippocampal slices: A patch-clamp study

J. Physiol.

Characterization of [3H]dopamine uptake sites and [3H]cocaine recognition sites in primary cultures of mesencephalic neurons during in vitro development

J. Neurochem.

Calcium current activation kincties in isolated pyramidal neurones of the Cal region of the mature guinea-pig hippocampus

J. Physiol.

K⁺-evoked dopamine release depends on a cytosolic Ca²⁺ pool regulated by N-type Ca²⁺ channels

Distribution of Ca²⁺ channels on frog motor nerve terminals revealed by fluorescent ω-conotoxin

Gangliosides normalize distorted single-cell intracellular free Ca²⁺ dynamics after toxic doses of glutamate in cerebellar granule cells

Characterization of [³H]dopamine uptake sites and [³H]cocaine recognition sites in primary cultures of mesencephalic neurons during in vitro development