ς₂-Receptor Regulation of Dopamine Transporter via Activation of Protein Kinase C

Abstract

The elucidation of the mechanisms underlying 2 -receptor activation and signal transduction is crucial to the understanding of 2 -receptor function. Previous studies in our laboratory have demonstrated 2 -receptor-mediated regulation of the dopamine transporter (DAT) as measured by amphetamine-stimulated release of [ -Receptors were first identified in 1976 by Martin et al. (1976) as the sites through which the psychotomimetic effects of SKF10,047 were mediated. Since that time, progress in identifying their physiological function(s) has been relatively slow compared with other receptor systems. There are at least two types of -receptors, designated 1 and 2 (Hellewell and Bowen, 1990;Quirion et al., 1992). -Receptors are distributed widely in the periphery and central nervous system (Walker et al., 1990). In brain, they are localized especially in motor and limbic systems (Gundlach et al., 1986), areas typically subserved by catecholaminergic neurotransmission. 1 -and 2 -receptors are colocalized in most regions, and have been reported to be present in a ratio of 4.3:1 in striatum (Bouchard and Quirion, 1997). 1 -Receptors were cloned first from guinea pig liver by Hanner et al. (1996) and the corresponding human gene further characterized by Prasad et al. (1998).1 -Receptors have been associated with second messenger activation and inhibition in several model systems. There is disagreement whether 1 -receptors are coupled through G

Steroids ModulateN-Methyl-D-aspartate-Stimulated [3H]Dopamine Release from Rat Striatum via σ Receptors

“…GF109203x, a PKC inhibitor, abolished 2 receptor-mediated regulation of dopamine transporter activity (Derbez et al, 2002). Morin-Surin et al (1999) showed a parallel translocation of receptors and PKC␤I and PKC␤II from the cytosol to the plasma membrane upon agonist application.…”

Synthesis and Pharmacological Evaluation of 6-Acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), a Cocaine Antagonist, in Rodents

“…First, during cocaine-induced sensitization, there are changes in the dopamine transporter and dopamine levels in the brain (54). Sigma receptors have been known to modulate dopamine transporter function and dopamine release via protein kinase C, the calcium/calmodulin-dependent kinase II system, ceramide, and changes in calcium levels (36,55,56). Second, activation of σ receptors can indirectly increase phosphorylation of CREB via ceramide, which is an important mediator of neuroadaptations in the brain (57)(58)(59).…”

ς1Receptor Agonist-Mediated Regulation ofN-Methyl-d-aspartate-Stimulated [3H]Dopamine Release Is Dependent upon Protein Kinase C

“…Treated n PMA (1 M) 9.5 Ϯ 0.90 10.6 Ϯ 1.5 3 Chelerythrine (5 M The relationship of receptor activation to Ca 2ϩ changes and IP 3 turnover, as well as evidence from our own laboratory demonstrating the abolition of 2 receptor-mediated regulation of dopamine transporter activity by the PKC inhibitor GF109203x (Derbez et al, 2002) suggests that the PKC signaling system could participate in 1 receptor-mediated regulation of vesicular dopamine release. PKC has been implicated in enhancement of release of other neurotransmitters (Majewski and Iannazzo, 1998), including adenosine and norepinephrine.…”

“…We reasoned that if receptors required an intact PKC signaling pathway, disruption of the pathway using PKC inhibitors should block the ability of receptor agonists to regulate stimulated [ 3 H]dopamine release. We have previously shown that 2 receptors were linked to dopamine transporter function via activation of a Ca 2ϩ -dependent PKC isozyme (Derbez et al, 2002). …”