Threonine 149 Phosphorylation Enhances ΔFosB Transcriptional Activity to Control Psychomotor Responses to Cocaine

Abstract

Stable changes in neuronal gene expression have been studied as mediators of addicted states. Of particular interest is the transcription factor ⌬FosB, a truncated and stable FosB gene product whose expression in nucleus accumbens (NAc), a key reward region, is induced by chronic exposure to virtually all drugs of abuse and regulates their psychomotor and rewarding effects. Phosphorylation at Ser 27 contributes to ⌬FosB's stability and accumulation following repeated exposure to drugs, and our recent work demonstrates that the protein kinase CaMKII␣ phosphorylates ⌬FosB at Ser 27 and regulates its stability in vivo. Here, we identify two additional sites on ⌬FosB that are phosphorylated in vitro by CaMKII␣, Thr 149 and Thr 180, and demonstrate their regulation in vivo by chronic cocaine. We show that phosphomimetic mutation of Thr 149 (T149D) dramatically increases AP-1 transcriptional activity while alanine mutation does not affect transcriptional activity when compared with wild-type (WT) ⌬FosB. Using in vivo viral-mediated gene transfer of ⌬FosB-T149D or ⌬FosB-T149A in mouse NAc, we determined that overexpression of ⌬FosB-T149D in NAc leads to greater locomotor activity in response to an initial low dose of cocaine than does WT ⌬FosB, while overexpression of ⌬FosB-T149A does not produce the psychomotor sensitization to chronic low-dose cocaine seen after overexpression of WT ⌬FosB and abrogates the sensitization seen in control animals at higher cocaine doses. We further demonstrate that mutation of Thr 149 does not affect the stability of ⌬FosB overexpressed in mouse NAc, suggesting that the behavioral effects of these mutations are driven by their altered transcriptional properties.

GIRK currents in VTA dopamine neurons control the sensitivity of mice to cocaine-induced locomotor sensitization

“…(Fig. 3A), using a typical dosage of 7.5 mg/kg cocaine that was shown previously to induce locomotor sensitization (39). Locomotor activity in SNX27 TH KO mice was significantly greater than that in SNX27 fl/fl or TH-Cre +/− controls, with a significant interaction between group and day (P < 0.0001) ( Fig.…”

Antidyskinetic Effects of MEK Inhibitor Are Associated with Multiple Neurochemical Alterations in the Striatum of Hemiparkinsonian Rats

“…First, ΔFosB lacks two critical degron domains, which are associated with ubiquitination and degradation in the C-terminus of full-length FosB and all other Fos family proteins. Second, ΔFosB is modified by some protein kinases at the N-terminus, adding further stability to the protein (Ulery et al, 2006; Gajewski et al, 2009; Ulery-Reynolds et al, 2009; Cates et al, 2014). Therefore, ΔFosB proteins tend to accumulate in neurons, and could persist for several weeks after withdrawal of relevant drug exposure.…”

∆FosB: A transcriptional regulator of stress and antidepressant responses

“…The stability of the ΔFosB isoforms provides a novel molecular mechanism by which stress-induced changes in gene expression can persist long after the stress exposure. ΔFosB is also phosphorylated at two threonine residues near its DNA-binding and transactivation domains, and phosphorylation of one of these sites (Thr149) dramatically increases the transcriptional activity of the protein (Cates et al, 2014). Further work is needed to define the role of these phosphorylation sites in stress responses.…”