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Vol. 52, Issue 6, 1095-1104, 1997
-Grammotoxin-SIA
Department of Neurobiology, Harvard Medical School, Boston,
Massachusetts 02115 (S.I.M., B.P.B.),
Vollum Institute, Oregon Health
Sciences University, Portland, Oregon 97201 (S.I.M., B.P.B), and
Department of Pharmacology, Zeneca Pharmaceuticals Group, Zeneca Inc.,
Wilmington, Delaware 19897 (R.A.L., R.A.K.)
We studied the mechanism by which the peptide 
-grammotoxin-SIA
inhibits voltage-dependent calcium channels. Grammotoxin at concentrations of >50 nM completely inhibited inward
current carried by 2 mM barium through P-type channels in
rat cerebellar Purkinje neurons when current was elicited by
depolarizations up to +40 mV. However, outward current (carried by
internal cesium) elicited by depolarizations to >+100 mV was either
unaffected or enhanced in the presence of toxin. Tail current
activation curves showed that grammotoxin shifted the steady state
voltage dependence of channel activation by 
+40 mV. Activation in
the presence of toxin was far slower in addition to having altered
voltage dependence. Grammotoxin also inhibited N-type calcium channels
in rat and frog sympathetic neurons, with changes in channel voltage
dependence and kinetics nearly identical to those of P-type channels.
Experiments with monovalent ions as the only charge carriers showed
that toxin effects on channel activation and kinetics depended on
voltage, not on direction of current flow or on the current-carrying
ion. Repeated trains of large depolarizations relieved toxin
inhibition, as if toxin affinity for activated channels were low. The
effects of grammotoxin on gating of P-type channels are very similar to those of -Aga-IVA, but combined application of the two toxins showed
that grammotoxin binding is not prevented by saturating binding of
-Aga-IVA. We conclude that grammotoxin potently inhibits both P-type
and N-type channels by impeding channel gating and that grammotoxin
binds to distinct or additional sites on P-type channels compared with
-Aga-IVA.
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