Sigma-1 receptors do not regulate calcium influx through voltage-dependent calcium channels in mouse brain synaptosomes

Several lines of evidence suggest that σ1 receptors regulate intracellular calcium concentration [Ca2 +]i. However, no previous studies have demonstrated a consistent role for these receptors in the modulation of extracellular calcium entry through plasmalemmal voltage-dependent calcium channels (VDCCs). To search for evidence of such a role we compared [Ca2 +]i under basal conditions and after depolarization with KCl in fura-2-loaded synaptosomes from wild-type and σ1 receptor knockout (σ1R-KO) mice. We also tested the effects of the selective σ1 receptor agonists PRE-084 and (+)-pentazocine and antagonists BD-1047 and NE-100 on the increase in [Ca2 +]i induced by depolarization with 60 mM KCl. Mibefradil, a nonselective blocker of VDCCs, was used as a positive control. Basal [Ca2 +]i and the increase in [Ca2 +]i caused by KCl-induced depolarization were similar in brain synaptosomes from both wild-type and σ1R-KO mice. Mibefradil (1–30 μM) and all σ1 receptor ligands studied (3–100 μM) inhibited the KCl-induced increase in [Ca2 +]i in a concentration-dependent way. The order of maximum inhibition for the ligands compared here was NE-100 > BD-1047 = PRE 084 > (+)-pentazocine. There were no appreciable differences in their effects between wild-type and σ1R-KO mice. These findings indicate that σ1 receptors are not involved in calcium influx through VDCCs or in the inhibitory effects of these σ1 ligands on Ca2 + channels.