Inhibition of calcium channels in rat central and peripheral neurons by omega-conotoxin MVIIC.
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.
McDonough
S I
SI
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Swartz
K J
KJ
Mintz
I M
IM
Boland
L M
LM
Bean
B P
BP
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005728:Ganglia, Sympathetic / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D009553:Nimodipine / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects*; D051381:Rats; D020960:omega-Conotoxins
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D010455:Peptides; D020960:omega-Conotoxins; C075851:omega-conotoxin-MVIIC; D009553:Nimodipine