Dopaminergic regulation of dopamine D3 and D3nf receptor mRNA expression

Abstract

Dopamine D3 receptors have the highest dopamine affinity of all dopamine receptors, and may thereby regulate dopamine signaling mediated by volume transmission. Changes in D3 receptor isoform expression may alter D3 receptor function, however little is known regarding coordination of D3 isoform expression in response to perturbations in dopaminergic stimulation. In order to determine the effects of dopamine receptor stimulation and blockade on D3 receptor alternative splicing, we determined D3 and D3nf isoform mRNA expression following treatment with the D3 receptor antagonist NGB 2904, and the indirect dopamine agonist amphetamine. Expression of tyrosine hydroxylase (TH) mRNA, the rate-limiting enzyme in dopamine synthesis, was also determined. The D3/D3nf mRNA expression ratio was increased in ventral striatum, prefrontal cortex and hippocampus six hours following D3 antagonist NGB 2904 treatment, and remained persistently elevated at 24 hours in hippocampus and substantia nigra/ ventral tegmentum. D3 mRNA decreased 65% and D3nf mRNA expression decreased 71% in prefrontal cortex 24 hours following amphetamine treatment, however these changes did not reach statistical significance. TH mRNA expression was unaffected by D3 antagonist NGB 2904, but was elevated by amphetamine in ventral striatum, hippocampus and prefrontal cortex. These findings provide evidence for an adaptive response to altered D3 receptor stimulation involving changes in D3 receptor alternative splicing. Additionally, these data suggest D3 autoreceptor regulation of dopamine synthesis does not involve regulation of TH mRNA expression. Finally, the observation of regulated TH mRNA expression in dopamine terminal fields provides experimental support for the model of local control of mRNA expression in adaptation to synaptic activity.

Upregulation of D2-class signaling in dopamine-denervated striatum is in part mediated by D3receptors acting on CaV2.1 channels via PIP2depletion

“…Changes in the expression of D 3 nf could be associated with the reduced activation of D 3 R after DA depletion, as has been suggested for D 2 R activity, which regulates the expression of its splicing isoforms D 2L R and D 2S R (Sasabe et al 2011). In support of this hypothesis, it was recently reported that D 3 nf levels in the brain are influenced by DA signals: D 3 R mRNA expression was not modified after its blockade, although D 3 nf mRNA was reduced (Richtand et al 2010), leading to an increase in the D 3 R-to-D 3 nf mRNA ratio during the "hypodopaminergic state" (Richtand et al 2010). This result closely matches our biochemical and pharmacological findings.…”

Coexistence of D3R typical and atypical signaling in striatonigral neurons during dopaminergic denervation. Correlation with D3nf expression changes

“…Our data suggest that changes in the expression of D 3 nf isoform are most likely responsible. According to the model proposed by Richtand et al (2010) and Karpa et al (2000), dimerization of D 3 nf isoform with D 3 R, sequester the latter into the cytoplasm preventing its location on membrane and signaling. On the contrary, according to Elmhurst et al (2000), the interaction can occur at the cytoplasmic membrane and also prevents D 3 R signaling.…”

“…On the contrary, it has been proposed that surface expression (Karpa, Lin, Kabbani, & Levenson, 2000) and function (Elmhurst, Xie, O'Dowd, & George, 2000) of D 3 R depends on the expression of its truncated splice variant named D 3 nf (Liu, Bergson, Levenson, & Schmauss, 1994), a protein with similar levels as canonical one (Liu et al, 1994) and that does not bind dopamine (Richtand, 2006). D 3 nf dimerizes with the canonical D 3 R sequestering them in the cytoplasm (Richtand et al, 2010) or interacting with these in the membrane (Elmhurst et al, 2000), preventing their signaling and regulating their interaction with other receptors, such as D 1 R (Richtand et al, 2010). Moreover, expression of D 3 nf protein decreases in experimental Parkinson (Prieto et al, 2011), which increases D2‐like inhibitory responses on Ca 2+ currents of striatopallidal neurons (Prieto et al, 2011).…”

Neurochemical and Behavioral Features in Genetic Absence Epilepsy and in Acutely Induced Absence Seizures

“…At the second stage, the modifications established at the first stage are consolidated through the modification of expression of the respective genes. The ability of DA receptors to undergo automodifications has been demonstrated both at the level of radioligand binding and at the level of gene expression in various brain structures and various experimental procedures [319, 442–447]. …”