Therapeutically relevant concentrations of neomycin selectively inhibit P-type Ca2+ channels in rat striatum.
The effects of neomycin on voltage-activated Ca(2+) channels (VACCs) were studied by Ca(2+)-dependent K(+)- and veratridine-evoked [3H]dopamine release from rat striatal slices. Neomycin (0.01-1 mM) concentration dependently reduced K(+)-evoked [3H]dopamine release (IC(50) approximately 25 microM), producing approximately 98% inhibition at 1 mM. Contribution of N-, P- and Q-type Ca(2+) channels to this neomycin-sensitive [3H]dopamine release was tested by the combined application of 100 microM neomycin and selective Ca(2+) channel blockers. The effects of neomycin combined with 1 microM of omega-conotoxin GVIA (N-type Ca(2+) channels) or with 100 nM of omega-conotoxin MVIIC (Q-type Ca(2+) channels) were additive, excluding involvement of N- and Q-type Ca(2+) channels. However, the combined effects of neomycin with 30 nM of omega-agatoxin-IVA (P-type Ca(2+) channels) were not additive, suggesting involvement of P-type Ca(2+) channels in neomycin-induced inhibition of [3H]dopamine release. On the other hand, veratridine-evoked [3H]dopamine release was shown to be mediated by Q-type Ca(2+) channels only. In addition, neither the inhibitor of sarcoplasmic reticulum Ca(2+)-ATPase thapsigargin (500 nM) nor the blocker of sarcoplasmic reticulum ryanodine Ca(2+) channels ryanodine (30 microM) modulate veratridine-evoked [3H]dopamine release, suggesting no contribution of intracellular Ca(2+) stores. Neomycin (up to 100 microM) did not affect veratridine-evoked [3H]dopamine release, suggesting that intracellular Ca(2+) stores are not a prerequisite for the action of neomycin. Lack of inhibitory effect of neomycin is taken as additional indirect evidence for the involvement of P-type Ca(2+) channels. In conclusion, therapeutically relevant concentrations of neomycin preferentially block P-type Ca(2+) channels which regulate dopamine release in rat striatum. This block could be responsible for aminoglycoside-induced toxicity.
Dobrev
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Department of Pharmacology and Toxicology, Carl Gustav Carus Medical School, Dresden University of Technology, Fetscher Str 74, D-01307 Dresden, Germany. dobrev@rcs1.urz.tu-dresden.de
Ravens
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D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000187:drug effects / Q000502:physiology; D020865:Calcium Channels, P-Type / Q000187:drug effects / Q000502:physiology*; D020907:Calcium Channels, Q-Type / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D009355:Neomycin / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014316:Tritium; D014701:Veratridine / Q000494:pharmacology; D020867:omega-Agatoxin IVA / Q000494:pharmacology; D020866:omega-Conotoxin GVIA / Q000494:pharmacology; D020960:omega-Conotoxins / Q000494:pharmacology
D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D020867:omega-Agatoxin IVA; D020960:omega-Conotoxins; D014316:Tritium; C075851:omega-conotoxin-MVIIC; D014701:Veratridine; D020866:omega-Conotoxin GVIA; D009355:Neomycin; D011188:Potassium; D002118:Calcium; D004298:Dopamine