ω-conotoxin MVIIC reversibly inhibits a human N-type calcium channel and calcium influx into chick synaptosomes

Grantham, C.J.; Bowman, D. M. J. S.; Bath, Catherine P.; Bell, Damian C.; Bleakman, David

doi:10.1016/0028-3908(94)90017-5

Cited by 54 publications

(32 citation statements)

References 6 publications

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“…Neither the first, nor the second relaxant phase was influenced. However, it is puzzling that o-conotoxin MVIIC was without effect, since the toxin has been demonstrated to inhibit, reversibly, N-type Ca2+ channels in chick synaptosomes (Grantham et al, 1994). co-Conotoxin MVIIC has in fact been shown to be even more effective than co-conotoxin GVIA in inhibiting NANC relaxation in rabbit urethral lamina propria .…”

Section: Discussionmentioning

confidence: 99%

Factors involved in the relaxation of female pig urethra evoked by electrical field stimulation

Werkström

Persson

et al. 1995

British J Pharmacology

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1 Non-adrenergic, non-cholinergic (NANC) relaxations induced by electrical field stimulation (EFS) were studied in pig isolated urethra. The mechanism for relaxation was characterized by measurement of cyclic nucleotides and by study of involvement of different subsets of voltage-operated calcium channels (VOCCs). 2 EFS evoked frequency-dependent and tetrodotoxin-sensitive relaxations in the presence of propranolol (1 yM), phentolamine (1 pM) and scopolamine (1 pM). At low frequencies (< 12 Hz), relaxations were rapid, whereas at high (> 12 Hz) frequencies distinct biphasic relaxations were evoked. The latter consisted of a rapidly developing first phase followed by a more long-lasting second phase. 3 Treatment with the NO-synthesis inhibitor N0-nitro-L-arginine (L-NOARG; 0.3 mM) inhibited relaxations at low frequencies of stimulation. At high frequencies (> 12 Hz) only the first relaxation phase was affected. 4 Measurement of cyclic nucleotides in preparations subjected to continuous nerve-stimulation, revealed an increase in guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels from 1.3 ± 0.3 to 3.0±0.4 pmol mg'-protein (P<0.01). In the presence of L-NOARG, there was a significant decrease in cyclic GMP content to control. However, there was no increase in cyclic GMP content in response to EFS. Levels of cyclic AMP remained unchanged following EFS. 5Treatment with the N-type VOCC-inhibitor, wo-conotoxin GVIA (0.1 FM) reduced NO-dependent relaxations, the effect being most pronounced at low frequencies (1-4 Hz) of stimulation. The NOindependent second phase of the relaxation, studied in the presence of L-NOARG (0.3 mM) at 16-30 Hz, was however markedly reduced or abolished by w-conotoxin GVIA. w-Conotoxin MVIIC (1 pM) or w-agatoxin IVA (30 nM) had no effect on electrically evoked relaxations. 6 These results suggest that NANC-nerve derived urethral relaxation in the pig consists of two apparently independent components. One is mediated by NO and associated with an increase in cyclic GMP content. The other mediator is unknown and produces relaxations not associated with changes in levels of cyclic nucleotides. The release of this mediator seems to involve the N-type VOCC, since the relaxation was markedly reduced or abolished by w-conotoxin GVIA.

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Section: Discussionmentioning

confidence: 99%

Factors involved in the relaxation of female pig urethra evoked by electrical field stimulation

Werkström

Persson

et al. 1995

British J Pharmacology

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“…In contrast, co-conotoxin GVIA, a toxin specific for the N-type Ca2" channel (Olivera et al, 1985;McCleskey et al, 1987), completely inhibited this positive inotropic response with an IC50 value similar to that of the block of other neuronal N-type Ca2" channels, suggesting that in the guinea-pig atrium the Ca2" channel of the sympathetic nerve activated by nerve action potential can be categorized as Ntype -the main Ca2" channel subtype proposed for other sympathetic nerves (Miller, 1987;Hirning et al, 1988;De Luca et al, 1990;Pruneau & Angus, 1990). A block of a major fraction of the positive inotropic response by o-conotoxin MVIIC, a blocker of OPQ subfamily and N-type Ca2" channels (Hillyard et al, 1992;Randall et al, 1993;Sather et al, 1993;Grantham et al, 1994;Olivera et al, 1994) can be attributed to its inhibition of the N-type Ca2+ channels. In contrast to the effect induced by electrical stimulation, the positive inotropic/chronotropic responses produced by the chemical stimulant DMPP were much less sensitive to both conopeptides.…”

Section: Discussionmentioning

confidence: 99%

Calcium channel subtypes for the sympathetic and parasympathetic nerves of guinea‐pig atria

Hong

Chang

1995

British J Pharmacology

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1 The Ca2" channel subtypes of the autonomic nerves of guinea-pig atria were elucidated by monitoring the effects of specific Ca2+ channel blockers on the negative and positive inotropic responses associated respectively, with stimulation of the parasympathetic and sympathetic nerves. 2 In left atria paced at 2-4 Hz, the negative inotropic effect induced by field stimulation of parasympathetic nerves (in the presence of propranolol) was abolished by w-conotoxin MVIIC, a blocker of N-type and OPQ subfamily Ca2" channels. .o-Conotoxin GVIA (an N-type blocker), o-agatoxin IVA (a P-type blocker), nifedipine (an L-type blocker) and Ni2+ (a T-and R-type blocker) were much less effective. 3 The positive inotropic response resulting from field stimulation of the sympathetic nerves (in the presence of atropine) was abolished by both co-conotoxins, while co-agatoxin IVA, nifedipine and Ni2+ were ineffective. 4 In the spontaneously beating right atria, the early negative inotropic effect produced by 1,1-dimethyl-4-phenylpiperazinium was abolished by co-conotoxin MVIIC; whereas the late positive inotropic effect was partially reduced, but not abolished, by a high concentration of o-conotoxin GVIA. 5 None of the peptide toxins affected the chronotropic and the inotropic responses evoked by carbachol and isoprenaline. 6 These results suggested that, under physiological conditions, the release of acetylcholine from paraysmpathetic nerves is dominated by an OPQ subfamily Ca2+ channel while that of noradrenaline from sympathetic nerves is controlled by an N-type Ca2+ channel. Ligand-induced noradrenaline release appeared to recruit additional type(s) of Ca2+ channel.

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“…Two factors could account for the prolonged duration of action of the toxins in these experiments. The binding of -CTX-G and -CTX-M to N-type calcium channels under ordinary condition is extremely stable, and it is generally considered to be irreversible (Cruz and Olivera, 1986;Grantham et al, 1994;Fox, 1995). If the turnover of N-type calcium channels is low (or if toxin binding inhibits turnover), then the irreversible nature of toxin binding could account for the persistent blocking action of the toxin.…”

Section: Ced Of Conotoxins In Kindling 465mentioning

confidence: 99%

Prolonged Attenuation of Amygdala-Kindled Seizure Measures in Rats by Convection-Enhanced Delivery of the N-Type Calcium Channel Antagonists ω-Conotoxin GVIA and ω-Conotoxin MVIIA

Gąsior

White

Rogawski³

2007

J Pharmacol Exp Ther

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Convection-enhanced delivery (CED) permits the homogeneous distribution of therapeutic agents throughout localized regions of the brain parenchyma without causing tissue damage as occurs with bolus injection. Here, we examined whether CED infusion of the N-type calcium channel antagonists -conotoxin GVIA (-CTX-G) and -conotoxin MVIIA (-CTX-M) can attenuate kindling measures in fully amygdala-kindled rats. Rats were implanted with a combination infusion cannula-stimulating electrode assembly into the right basolateral amygdala. Fully kindled animals received infusions of vehicle, -CTX-G (0.005, 0.05, and 0.5 nmol), -CTX-M (0.05, 0.15, and 0.5 nmol), proteolytically inactivated -CTX-M (0.5 nmol), or carbamazepine (500 nmol) into the stimulation site. CED of -CTX-G and -CTX-M over a 20-min period resulted in a dose-dependent increase in the afterdischarge threshold and a decrease in the afterdischarge duration and behavioral seizure score and duration during a period of 20 min to 1 week after the infusion, indicating an inhibitory effect on the triggering and expression of kindled seizures. The protective effects of -conotoxins reached a maximum at 48 h postinfusion, and then they gradually resolved over the next 5 days. In contrast, carbamazepine was active at 20 min but not at 24 h after the infusion, whereas CED of vehicle or inactivated -CTX-M had no effect. Except for transient tremor in some rats receiving the highest toxin doses, no adverse effects were observed. These results indicate that local CED of high-molecular-weight presynaptic N-type calcium channel blockers can produce long-lasting inhibition of brain excitability and that they may provide prolonged seizure protection in focal seizure disorders.

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ω-conotoxin MVIIC reversibly inhibits a human N-type calcium channel and calcium influx into chick synaptosomes

Cited by 54 publications

References 6 publications

Factors involved in the relaxation of female pig urethra evoked by electrical field stimulation

Factors involved in the relaxation of female pig urethra evoked by electrical field stimulation

Calcium channel subtypes for the sympathetic and parasympathetic nerves of guinea‐pig atria

Prolonged Attenuation of Amygdala-Kindled Seizure Measures in Rats by Convection-Enhanced Delivery of the N-Type Calcium Channel Antagonists ω-Conotoxin GVIA and ω-Conotoxin MVIIA

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