Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Jul;30(4):351-357.
doi: 10.1111/ajad.13150. Epub 2021 Mar 30.

β-Arrestin 2 (ARRB2) Polymorphism is Associated With Adverse Consequences of Chronic Heroin Use

Klevis K Karavidha  1 , Margit Burmeister  2 , Mark K Greenwald  1   3
Affiliations

β-Arrestin 2 (ARRB2) Polymorphism is Associated With Adverse Consequences of Chronic Heroin Use

Klevis K Karavidha et al. Am J Addict. 2021 Jul.

Abstract

Background and objectives: β-arrestin 2 is an intracellular protein recruited during the activation of G-protein-coupled receptors. In preclinical studies, β-arrestin 2 has been implicated in µ-opioid receptor desensitization and internalization and the development of opioid tolerance and dependence. The present study investigated relationships between variants in the gene encoding β-arrestin 2 (ARRB2) and clinically relevant phenotypes among individuals with opioid use disorder (OUD). We hypothesized that ARRB2 variants would be associated with the negative effects of long-term heroin use.

Methods: Chronic heroin users (N = 201; n = 103 African American; n = 98 Caucasian) were genotyped for ARRB2 r1045280 (synonymous, also affecting binding motif of transcription factor GTF2IRD1), rs2036657 (3'UTR) and rs3786047 (intron) and assessed for the past-month frequency of use, injection use, and lifetime duration of heroin use, number of heroin quit-attempts, and heroin use-related consequences.

Results: Lifetime heroin-use consequences (especially occupational and health-related) were significantly lower for African American ARRB2 r1045280 C-allele carriers compared with the TT genotype. There was no significant genotype difference in the Caucasian group. ARRB2 rs2036657 was in strong linkage disequilibrium with rs1045280.

Discussion and conclusions: These results, consistent with extant data, illustrate a role for ancestry-dependent allelic variation in ARRB2 r1045280 on heroin-use consequences. The ARRB2 r1045280 C-allele played a protective role in African-descent participants.

Scientific significance: These first-in-human findings, which should be replicated, provide support for mechanistic investigations of ARRB2 and related intracellular signaling molecules in OUD etiology, treatment, and relapse prevention. (Am J Addict 2021;00:00-00).

PubMed Disclaimer

Conflict of interest statement

Declaration of Interest

All authors declare no conflict of interest with respect to the conduct or content of this work. Unrelated to this manuscript, MKG has received honoraria and consulting fees from Indivior Inc., Supernus Pharmaceuticals Inc., and Nirsum Labs.

Figures

Figure 1.
Figure 1.
Association of ARRB2 rs1045280 genotype, stratified by ancestral group, with mean ± 1 SD total heroin use consequences. Asterisk indicates significant difference between the TT group (n=24) and the CT (n=58) and CC (n=21) groups (Bonferroni post hoc test following ANOVA in African Americans only). There were no significant differences between TT (n=47), CT (n=39) and CC (n=12) groups among Caucasian participants.
Figure 2.
Figure 2.
Association of ARRB2 rs1045280 genotype (African Americans only) with mean ±1 SD heroin use-related acute health and occupational consequences. Asterisks indicate significant difference between the TT group (n=24) and CT (n=58) and CC (n=21) genotypes (Bonferroni post hoc comparison following ANOVA).
See this image and copyright information in PMC

References

    1. Porter-Stransky KA, Weinshenker D. Arresting the development of addiction: the role of beta-arrestin 2 in drug abuse. J Pharmacol Exp Ther. 2017;361(3):341–348. - PMC - PubMed
    1. Derouiche L, Massotte D. G protein-coupled receptor heteromers are key players in substance use disorder. Neurosci Biobehav Rev. 2019;106:73–90. - PubMed
    1. Gurevich VV, Gurevich EV. The molecular acrobatics of arrestin activation. Trends Pharmacol Sci. 2004;25(2):105–111. - PubMed
    1. Mores KL, Cassell RJ, van Rijn RM. Arrestin recruitment and signaling by G protein-coupled receptor heteromers. Neuropharmacology. 2019;152:15–21. - PMC - PubMed
    1. Groer CE, Schmid CL, Jaeger AM, Bohn LM. Agonist-directed interactions with specific beta-arrestins determine mu-opioid receptor trafficking, ubiquitination, and dephosphorylation. J Biol Chem. 2011;286(36):31731–31741. - PMC - PubMed

Publication types

Substances