Sigma-1 receptors amplify dopamine D1 receptor signaling at presynaptic sites in the prelimbic cortex

Sigma-1 receptors are highly expressed in the brain. The downstream signaling mechanisms associated with the sigma-1 receptor activation have been shown to involve the activation of protein kinase C (PKC), the control of Ca² homoeostasis and the regulation of voltage- and ligand-gated ion channels. But few studies examined the regulatory effect of sigma-1 receptors on metabotropic receptor signaling. The present paper studied the regulatory effect of sigma-1 receptors on the signaling of dopamine D1 receptors, one of metabotropic receptors, by examining the effect of sigma-1 receptor agonists on the D1 receptor agonist-induced cAMP-dependent protein kinase (PKA) activation at presynaptic sites using the synaptosomes from the prelimbic cortex. The results showed that sigma-1 receptor agonists alone had no effects on the PKA activity, but could amplify the D1 receptor agonist-induced PKA activation. The sigma-1 receptor agonist also amplified the membrane-permeable analog of cAMP- and the adenylyl cyclase (AC) activator-induced PKA activation, but did not on the D1 receptor agonist-induced AC activation. The conventional PKC (cPKC), especially the PKCβI, and the extracellular Ca²⁺ influx through L-type Ca²⁺ channels might play key roles in the amplifying effect of the sigma-1 receptor agonists. The activation of PKC by sigma-1 receptor agonists was the upstream event of the increase in the intrasynaptosomal Ca²⁺ concentration. These results suggest that sigma-1 receptors may amplify the D1 receptor agonist-induced PKA activation by sigma-1 receptors - cPKC (especially the PKCβI) - L-type Ca²⁺ channels - Ca²⁺ - AC and/or cAMP signaling pathway.