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Inhibition of calcium channels in rat central and peripheral neurons by omega-conotoxin MVIIC
S I McDonough1, K J Swartz, I M Mintz
1Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
Inhibition of voltage-dependent calcium channels by omega-conotoxin MVIIC (omega-CTx-MVIIC) was studied in various types of rat neurons. When studied with 5 mM Ba2+ as charge carrier, omega-CTx-MVIIC block of N-type calcium channels in sympathetic neurons was potent, with half-block at 18 nM. Block of N-type channels had a rapid onset (tau approximately 1 sec at 1 microM omega-CTx-MVIIC) and quick reversibility (tau approximately 30 sec). The rate of block was proportional to toxin concentration, consistent with 1:1 binding of toxin to channels, with a rate constant (k on) of approximately 1 X 10(6) M-1. sec-1. Both potency and rate of block were reduced dramatically with increasing concentrations of extracellular Ba2+ omega-CTx-MVIIC also blocked P-type calcium channels in cerebellar Purkinje neurons, but both development and reversal of block were far slower than for N-type channels. The rate of block was proportional to toxin concentration, with k on -1.5 x 10(3) M-1. sec-1 at 5 mM Ba2+. From this value and an unblocking time constant of approximately 200 min, a dissociation constant of approximately 50 nM was estimated. Thus, block of P-type channels is potent but very slow. In hippocampal CA3 pyramidal neurons, omega-CTx-MVIIC blocked approximately 50% of the high-threshold calcium channel current; one component (approximately 20%) was blocked with the rapid kinetics expected for N-type channels, whereas the other component was blocked slowly. The component blocked slowly was reduced but not eliminated by preexposure to 200 nM or 1 microM omega-Aga-IVA.
Insights
Omega-conotoxin MVIIC (omega-CTx-MVIIC) potently inhibits N-type calcium channels in sympathetic neurons but slowly blocks P-type channels in Purkinje neurons. This toxin exhibits differential effects on various neuronal calcium channel subtypes.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Voltage-dependent calcium channels (VGCCs) are crucial for neuronal function.
- Omega-conotoxins are peptide toxins that selectively modulate VGCCs.
- Understanding toxin-channel interactions aids in developing therapeutic agents.
Purpose of the Study:
- To investigate the inhibitory effects of omega-conotoxin MVIIC (omega-CTx-MVIIC) on different types of rat neurons.
- To characterize the kinetics and potency of omega-CTx-MVIIC block on N-type and P-type calcium channels.
- To explore the differential sensitivity of neuronal calcium channel subtypes to omega-CTx-MVIIC.
Main Methods:
- Electrophysiological recordings in various rat neuronal preparations.
- Application of omega-conotoxin MVIIC at varying concentrations.
- Use of barium ions (Ba2+) as charge carriers.
- Kinetic analysis of toxin-induced channel block and recovery.
Main Results:
- Omega-CTx-MVIIC potently and rapidly blocked N-type calcium channels in sympathetic neurons (half-block at 18 nM).
- Block of P-type calcium channels in Purkinje neurons by omega-CTx-MVIIC was potent but significantly slower (dissociation constant ~50 nM).
- In hippocampal CA3 pyramidal neurons, omega-CTx-MVIIC showed mixed block kinetics, affecting both N-type and slowly blocked components.
Conclusions:
- Omega-CTx-MVIIC displays differential potency and kinetics for inhibiting distinct neuronal calcium channel subtypes.
- The toxin's interaction with N-type channels is rapid and reversible, while P-type channel block is slow but potent.
- These findings highlight the potential of omega-CTx-MVIIC as a selective pharmacological tool for studying calcium channel function.
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