ELK1 transcription factor linked to dysregulated striatal mu opioid receptor signaling network and OPRM1 polymorphism in human heroin abusers.
- Authors
- Daws, Stephanie E; Whittard, John D; Jacobs, Michelle M; Ren, Yanhua; Mazloom, Amin R; Caputi, Francesca F; Horvath, Monika; Keller, Eva; Ma'ayan, Avi; Pan, Ying-Xian; Chiang, Lillian W; Hurd, Yasmin L
- Year
- 2013
- Journal
- Biological psychiatry
- PMID
- 23702428
- DOI
- 10.1016/j.biopsych.2013.04.012
- PMCID
- PMC4070524
BACKGROUND: Abuse of heroin and prescription opiate medications has grown to disturbing levels. Opioids mediate their effects through mu opioid receptors (MOR), but minimal information exists regarding MOR-related striatal signaling relevant to the human condition. The striatum is a structure central to reward and habitual behavior and neurobiological changes in this region are thought to underlie the pathophysiology of addiction disorders. METHODS: We examined molecular mechanisms related to MOR in postmortem human brain striatal specimens from a homogenous European Caucasian population of heroin abusers and control subjects and in an animal model of heroin self-administration. Expression of ets-like kinase 1 (ELK1) was examined in relation to polymorphism of the MOR gene OPRM1 and drug history. RESULTS: A characteristic feature of heroin abusers was decreased expression of MOR and extracellular regulated kinase signaling networks, concomitant with dysregulation of the downstream transcription factor ELK1. Striatal ELK1 in heroin abusers associated with the polymorphism rs2075572 in OPRM1 in a genotype dose-dependent manner and correlated with documented history of heroin use, an effect reproduced in an animal model that emphasizes a direct relationship between repeated heroin exposure and ELK1 dysregulation. A central role of ELK1 was evidenced by an unbiased whole transcriptome microarray that revealed ~20% of downregulated genes in human heroin abusers are ELK1 targets. Using chromatin immune precipitation, we confirmed decreased ELK1 promoter occupancy of the target gene Use1. CONCLUSIONS: ELK1 is a potential key transcriptional regulatory factor in striatal disturbances associated with heroin abuse and relevant to genetic mutation of OPRM1.
MOR signaling networks and the MAPK pathway are dysregulated in human heroin abusers(A,B) Protein levels of MOR, β-arrestin2, MEK1, ERK1, ERK2, ELK1, and pELK1 in the putamen of human control subjects and heroin abusers. N=15 control, N=32 heroin. Representative bands are shown next to the histograms; Mean ± SEM. * p < 0.05, ** p < 0.01. (C) Schematic depiction of the MOR signaling networks. (D) Ratio of phosphorylated versus total ELK1 protein in human subjects. Abbreviations: C, CTL, control; H, HER, heroin.
LLM interpretation
This figure consists of protein expression data and a signaling diagram comparing human control subjects (CTL) and heroin abusers (HER). Panels A and B show a bar chart and corresponding western blot bands indicating that $\beta$-arrestin2, MEK1, ERK1, and pELK1 are significantly decreased, while ERK2 and ELK1 are significantly increased in the putamen of heroin abusers (*p < 0.05, **p < 0.01). Panel C provides a schematic of the MOR signaling pathway, and Panel D shows a significant decrease (**p < 0.01) in the ratio of phosphorylated ELK1 to total ELK1 in the heroin group.
ELK1 expression levels are increased in striatal regions in heroin abusers(A) A representative photomicrograph of striatal-mounted sections (20μm) after laser capture microdissection. Circular dark areas indicate striatal regions that were isolated. (B) ELK1 protein levels were significantly increased in all striatal regions in heroin abusers. Representative bands are shown below histograms; mean ± SEM. Abbreviations: CN, caudate; NAc, nucleus accumbens; PU, putamen. For Western analyses, N=15 control, N=32 heroin. * p < 0.05.
LLM interpretation
Figure A is a photomicrograph of a striatal section showing circular areas isolated via laser capture microdissection in the caudate (CN), putamen (PU), and nucleus accumbens (NAc). Figure B consists of three bar charts and corresponding Western blot bands showing ELK1 protein levels as a percentage of total protein. In all three regions (CN, PU, and NAc), ELK1 levels are higher in the heroin group compared to the control group, with statistical significance indicated by asterisks (* p < 0.05).
ELK1 expression levels are associated with polymorphism of the OPRM1 gene(A) Heroin subjects carrying the G allele of the rs1799971 SNP have highest the ELK1 expression. Control A/A, N=13; Heroin A/A, N=22, Heroin G, N=10. (B) Genotype-dose effect evident for the rs2075572 SNP in controls and heroin subjects with ELK1 expression levels highest in C/C subjects in each respective group. Control: C/C and C/G, N= 8 and 5, respectively; Heroin: C/C, C/G and G/G, N=8, 10 and 15, respectively. Mean ± SEM. * p < 0.05, ** p < 0.01.
LLM interpretation
This figure consists of two bar charts showing the percentage of ELK1 expression associated with different OPRM1 gene polymorphisms. Panel A shows that heroin subjects carrying the G allele of rs1799971 have significantly higher ELK1 expression compared to heroin A/A and control A/A groups (*p < 0.05). Panel B demonstrates a genotype-dose effect for rs2075572, with the highest expression levels observed in C/C subjects for both control and heroin groups, with significant differences noted between genotypes (*p < 0.05, **p < 0.01).
Striatal ELK1 protein levels correlate with heroin use(A) A strong positive correlation (r2=0.70) was observed between ELK1 protein expression in the putamen and urine levels of the rapid heroin metabolite 6-MAM in human heroin abusers; seven subjects had detectable 6-MAM levels. (B) ELK1 mRNA levels negatively correlate with the age of onset of heroin use in human subjects that carry the G allele of rs2075572 (r2=0.37), with the strongest correlation in G/G subjects (r2=0.95). (C) Total ELK1 protein levels in the dorsal striatum are positively correlated (r2=0.79) to history of heroin intake in a rat heroin self-administration model 1 hour after the last drug session, while a negative correlation (r2=0.72) was observed 24 hours later (D). N= 5–11/group.
LLM interpretation
This figure consists of four scatter plots with linear regression lines showing correlations between ELK1 expression and heroin use. Panel A shows a positive correlation between human putamen ELK1 protein expression and urine 6-MAM levels, while Panel B shows a negative correlation between ELK1 mRNA expression and age of heroin use onset in human G allele carriers. Panels C and D show that in rats, total heroin intake positively correlates with dorsal striatum ELK1 expression 1 hour after the last session, but negatively correlates 24 hours later.
Heroin inhibits ELK1 phosphorylation in a dose-dependent mannerA) Levels of phosphorylated ELK1 (pELK1; normalized to total protein or total ELK1) measured in the dorsal striatum of rats 1 hour or 24 hours after final heroin self-administration session. A representative blot is shown in Panel A. Levels pELK1 negatively correlated with each animal’s total heroin intake at both the 1 hour (r=.86) (B) and 24 hour (r=.79) (C) time points. Abbreviations: S, saline; H, heroin. N=5–6 animals/group. Mean ± SEM. * p < 0.05.
LLM interpretation
This figure consists of two bar charts, a representative western blot, and two scatter plots. The bar charts show that heroin significantly increases pELK1 levels relative to saline controls at 24 hours, but not at 1 hour, for both pELK1/total protein and pELK1/total ELK1 (*p < 0.05). The scatter plots (B and C) demonstrate a negative correlation between total heroin intake (µg) and pELK1/total protein levels at both the 1-hour and 24-hour time points.
Downregulation of ELK1 target genes after repeated heroin exposureA) Of the 195 down-regulated genes identified in heroin abusers, approximately 20% were classified as ELK1 putative targets using the List2Networks software analyses. Control N=27; heroin N=22. B) Downregulation of the ELK1 target genes BAG1 and USE1 was confirmed with Nanostring technologies in a subset of subjects. Additionally, ELK1 mRNA levels were increased in heroin subjects. Control N=16; heroin N=20. C) In a rat heroin self-administration model, decreased occupancy of ELK1 was detected at the promoter region of the target gene Use1 at 1 hour after the last heroin session but was normalized 24 hours after the last drug session. N=6–7 animals/group. Mean ± SEM. * p < 0.05, ** p < 0.01.
LLM interpretation
This figure consists of a Venn diagram and two bar charts analyzing ELK1 target genes in heroin exposure models. Panel A shows an overlap of 36 genes between 2,282 putative ELK1 targets and 195 downregulated genes in heroin abusers. Panel B displays a bar chart showing decreased mRNA expression of *BAG1* and *USE1* and increased expression of *ELK1* in heroin subjects compared to controls, with significance markers (* p < 0.05, ** p < 0.01). Panel C shows a bar chart of % input at the *Use1* TSS, indicating significantly decreased ELK1 occupancy in the heroin group compared to saline at 1 hour, which normalizes by 24 hours.
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