Neurotoxic aminoglycoside antibiotics are potent inhibitors of [125I]-Omega-Conotoxin GVIA binding to guinea-pig cerebral cortex membranes.
[125I]-Omega-Conotoxin GVIA, a blocker of neuronal (N-type) calcium channels labelled 295 +/- 121 fmol per mg protein of high affinity sites (apparent half-saturation at 1.5 to 2.5 pmol/l) in guinea-pig cerebral cortex membranes. Divalent cations (Cd2+ greater than Ni2+ greater than Co2+ greater than Ca2+ greater than Sr2+ = Ba2+ greater than Mg2+) and La3+ were potent inhibitors of Omega-Conotoxin GVIA binding, whereas monovalent cations (Na+, K+, Li+) were ineffective up to 50 mmol/l. Aminoglycosides (neomycin greater than gentamycin = tobramycin greater than streptomycin greater than amikacin greater than kanamycin) and polymyxin B also inhibited [125I]-Omega-Conotoxin GVIA binding with IC50 values in the mumolar range. All other antibiotics tested were ineffective up to 1 mmol/l. With the exception of polymyxin B, which partially inhibited the binding of the 1,4-dihydropyridine (+)-[3H]PN 200-110 and of (-)-[3H]desmethoxyverapamil, the aminoglycosides and the other antibiotics had no effect on the L-type calcium channel labelling. It is suggested, that inhibition of neurotransmitter release by aminoglycosides is mediated via blockade of the N-type calcium channel to which [125I]-Omega-Conotoxin GVIA binds selectively in a quasi irreversible manner.
Knaus
H G
HG
Institut für Biochemische Pharmakologie, Universität Innsbruck, Austria.
Striessnig
J
J
Koza
A
A
Glossmann
H
H
D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000633:toxicity; D002121:Calcium Channel Blockers / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism*; D006168:Guinea Pigs; D008978:Mollusk Venoms / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009420:Nervous System / Q000187:drug effects; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D014700:Verapamil / Q000031:analogs & derivatives / Q000378:metabolism; D020866:omega-Conotoxin GVIA
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D002121:Calcium Channel Blockers; D008978:Mollusk Venoms; D017981:Receptors, Neurotransmitter; D020866:omega-Conotoxin GVIA; C043184:4-desmethoxyverapamil; D014700:Verapamil