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The σ ligand 1,3‐di‐O‐tolylguanidine (DTG) increased basal dynamin and decreased depolarization‐stimulated phosphorylation of the synaptosomal protein synapsin Ib without having direct effects on protein kinases or protein phosphatases. DTG dose‐dependently decreased the basal cytosolic free Ca2+ concentration ([Ca2+]i) and blocked the depolarization‐dependent increases in [Ca2+]i. These effects were inhibited by the σ antagonists rimcazole and BMY14802. The nitric oxide donors sodium nitroprusside (SNP) and 8‐(p‐chlorophenylthio)guanosine‐3′,5′‐cyclic monophosphorothioate decreased basal [Ca2+]i and the KCl‐evoked rise in [Ca2+]i to an extent similar to DTG. SNP, but not DTG, produced a rise in cyclic GMP levels, suggesting that the effect of DTG on [Ca2+]i was not mediated via downstream regulation of cyclic GMP levels. DTG increased 45Ca2+ uptake and efflux under basal conditions and inhibited the 45Ca2+ uptake induced by depolarization with KCl. The KCl‐evoked rise in [Ca2+]i was inhibited by ω‐conotoxin (ω‐CgTx)‐GVIA and ‐MVIIC but not nifedipine and ω‐agatoxin‐IVA. The effect of DTG on decreasing the KCl‐evoked rise in [Ca2+]i was additive with ω‐CgTx‐MVIIC but not with ω‐CgTx‐GVIA. These data suggest that DTG was producing some of its effects on synapsin I and dynamin phosphorylation and intrasynaptosomal Ca2+ levels via inhibition of N‐type Ca2+ channels.

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