Protein Phosphorylation and Calcium Uptake into Rat Forebrain Synaptosomes: Modulation by the σ Ligand, 1,3‐Ditolylguanidine

Abstract

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.

The Role of Sigma Receptors in Depression

“…Thus the mobilization of intracellular Ca 2+ from IP 3 receptor-sensitive pools appears also to participate initially in the behavioral effects mediated by sigma 1 receptors located on the ER membranes (211). The sigma 1 receptor then putatively moves to the plasma membrane and interacts with VDCC's (31,60).…”

“…The molecular mechanism underlying sigma receptors' ability to modulate 5-HT and glutamatergic transmissions may involve sigma receptors' ability to modulate Ca 2+ (31,58,60,212) or K + signalling (43,50,54,213). This modulation could represent a downstream target involved in the effects of sigma ligands on both the glutamatergic and the 5-HT systems, thus leading to one primary target.…”

ς2-Receptor Regulation of Dopamine Transporter via Activation of Protein Kinase C

“…In our laboratory, we have not found evidence of direct coupling to G proteins Werling, 2000, 2001), but have not ruled out an indirect coupling. 1 -Receptors have been associated with calcium homeostasis (Brent et al, 1997;Klette et al, 1997;Hayashi et al, 2000).…”

Regulating ankyrin dynamics: Roles of sigma-1 receptors

“…Sig-1R have been shown to affect Ca 2ϩ signaling, although the exact molecular mechanism is unknown (24)(25)(26)(27)(28)(29)(30). For example, Sig-1R ligands affect intrasynaptosomal free Ca 2ϩ level and protein phosphorylation in rat brain (24).…”

“…For example, Sig-1R ligands affect intrasynaptosomal free Ca 2ϩ level and protein phosphorylation in rat brain (24). Sig-1R ligands also affect the N-methyl-D-aspartate-induced Ca 2ϩ signaling in rat primary neurons (25,26).…”