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

Abstract

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 Ca(2) 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 Ca(2+) influx through L-type Ca(2+) 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 Ca(2+) 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 Ca(2+) channels - Ca(2+) - AC and/or cAMP signaling pathway.

Sigma-1 Receptor Agonists Directly Inhibit NaV1.2/1.4 Channels

“…NDHEA sulfate, a sigma-1 receptor agonist, inhibits persistent sodium currents in the rat medial prefrontal cortex via the G i protein and the PKC signaling pathways [36]. The sigma-1 receptor ligand PRE-084 amplifies dopamine D1 receptor signaling in the prelimbic cortex [37]. G-protein blockade or activation using G i/o and G s inhibitors did not alter the (+)-SKF 10047 -induced inhibition of Na V 1.2 channel currents.…”

Decreases in Cocaine Self-Administration with Dual Inhibition of the Dopamine Transporter and σ Receptors

“…Previous studies have demonstrated an influence of membrane lipids on DAT trafficking (Foster et al, 2008) and transport capacity (Adkins et al, 2007). More recently, Hong and Amara (2010) have suggested on the basis of substituted cysteine accessibility methods that a cholesterol-rich membrane environment shifts the DAT conformational equilibrium toward a Fu et al (2010) indicates that the R agonist, PRE-084, which had no effects of its own, amplified the effects of the D 1 R partial agonist, SKF 38393. In addition, Navarro et al (2010) showed evidence supporting heteromerization of and dopamine D 1 receptors and a potentiation of D 1 R-mediated adenylyl cyclase activation by actions at Rs.…”

Overexpression of sigma-1 receptor inhibits ADAM10 and ADAM17 mediated shedding in vitro

“…Since ADAM10 function is induced by free Ca 2+ in cell (Sanderson et al, 2005;Horiuchi et al, 2007), such inhibition could thus inhibit ADAM10-dependent BTC shedding. On the other hand, although sigma-1 receptor agonists could activate PKC (Fu et al, 2010;Yoon et al, 2010) which can in turn activate ADAM17-dependent shedding (Zheng et al, 2002(Zheng et al, , 2004Sahin et al, 2004), such an effect might be covered by the Figure 3. ADAM10-depedent BTC shedding is more sensitive to membrane lipid change while ADAM17-dependent HB-EGF shedding was not.…”