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 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.
Fu
Yingmei
Y
State key Laboratory of Medical Neurobiology, Shanghai Medical College and Institutes of Brain Science, Fudan University, Shanghai, China.
Zhao
Yanyan
Y
Luan
Wenjie
W
Dong
Lian-Yian
LY
Dong
Yi
Y
Lai
Bin
B
Zhu
Yanhua
Y
Zheng
Ping
P
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D004789:Enzyme Activation; D008032:Limbic System / Q000378:metabolism*; D008297:Male; D017729:Presynaptic Terminals / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017480:Receptors, sigma / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D000097605:Sigma-1 Receptor
D002118:Calcium; D017868:Cyclic AMP-Dependent Protein Kinases; D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor