Sigma-1 Receptors Amplify Dopamine D₁ Receptor Signaling At Presynaptic Sites In The Prelimbic Cortex

Sigma-1 receptors amplify dopamine D1 receptor signaling at presynaptic sites in the prelimbic cortexSigma-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 PKC(3I)-L-type Ca2+ channels-Ca2+-AC and/or cAMP signaling pathway. PI-linked D1 receptors modulate classical dopamine D1 receptor/cAMP/PKA pathway at presynaptic sites in the prelimbic cortexInositol 1,4,5-trisphosphate (InsP3) and cAMP are the two second messengers that play an important role in neuronal signaling. Here, we investigated the interactions of InsP 3- and cAMP-mediated signaling pathways activated by dopamine at presynaptic sites in the prelimbic cortex. The present paper studied the regulatory effect of phosphatidylinositol (PI)-linked D1 -like receptor on the signaling of classical dopamine D1 receptors by examining the effect of PI-linked D1-like receptor agonists SKF83959 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 SKF83959 alone had no effects on the PKA activity, but could amplify the classical D1 receptor agonist-induced PKA activation. The conventional PKC (cPKC), especially the PKCa, and the extracellular Ca2+ influx, Phospho- DARPP-32 Thr75 also play key roles in the modulate effect of the SKF83959. These results suggest that PI-linked D1-like receptors may modulate the classical D1 receptor agonist-induced PKA activation by PI-linked D1-like receptors-cPKC (especially the PKCα)-Ca2+-Cdk5-Phospho- DAPRR-32 Thr 75 signaling pathway. This may provide a potential target for the drug discovery in Parkinson's disease.