# Contributions of aberrant synaptic protein monoaminylation to opiate use disorder

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $688,381

## Abstract

PROJECT SUMMARY
Opiate use, dependence and addiction represent enduring public health issues, resulting in substantial financial
and societal health burdens, as well as increasing numbers of overdoses. Drug addiction is characterized as a
chronic, relapsing disease. However, to date, there remains insufficient data examining the molecular
mechanisms underlying persistent opiate-induced neurobiological changes, which has led to a scarcity of
effective therapies and interventions to treat and prevent relapse.
 Drug addiction has long been thought of as a disorder of dopamine (DA) signaling. However, therapeutic
interventions targeting receptor mediated DA neurotransmission have not yet resulted in fully efficacious
treatments. Therefore, an overarching goal of our laboratories – and the focus of this application – has been to
investigate novel, non-canonical actions of DA involved in mediating addiction phenotypes. Our laboratory
recently identified a novel signaling moiety for DA in brain, termed dopaminylation (dop), whereby DA acts as
a donor source for the establishment of post-translational modifications (PTM) on substrate proteins (e.g.,
histone H3) via transamidation by the Transglutaminase 2 (TGM2) enzyme. In more recent efforts by our lab to
unbiasedly identify additional substrates of these PTMs (focused now on synaptic proteins in nucleus
accumbens/NAc, a key brain reward region), we developed a novel chemical tagging approach that, when
coupled to mass spectrometry, allowed for the discovery of hundreds of dopaminylated proteins in brain, both in
the context of normal neural function and in response to aberrant dopamine signaling following chronic heroin
self-administration (SA) in rats. Among them, gCaMKII: 1) was found to be robustly dopaminylated at only a
single amino acid residue located within its autoinhibitory helix [glutamine (Q)285], a site that exists only two
amino acids away from a critical threonine (T) residue (287), which when phosphorylated directs Calmodulin
(CaM) sequestration; 2) is upregulated in its dopaminylation following heroin SA, both during acute and
prolonged abstinence, but not in response to natural rewards; and 3) represents a critical substrate involved in
mediating long range signals from the synapse to nucleus in brain, ultimately promoting CREB activation and
neuronal plasticity. Thus, this dopaminylation event on gCaMKII may represent a critical convergent mechanism
linking altered dopaminergic signaling in response to heroin to CREB mediated transcriptional abnormalities. As
such, we hypothesize that gCaMKIIQ285dop may play a direct role in mediating heroin relapse via aberrant
modulation of CREB signaling in NAc. In Aim 1, we will fully characterize gCaMKIIQ285dop’s temporal effects
on drug taking vs. relapse vulnerability in the context of heroin SA. In Aim 2, we will explore gCaMKIIQ285dop’s
effects on CREB signaling/transcription following heroin SA, events that may precipitate relapse vulnerabi...

## Key facts

- **NIH application ID:** 10836016
- **Project number:** 5R01DA056595-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** DAVID M DIETZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $688,381
- **Award type:** 5
- **Project period:** 2022-08-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10836016

## Citation

> US National Institutes of Health, RePORTER application 10836016, Contributions of aberrant synaptic protein monoaminylation to opiate use disorder (5R01DA056595-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10836016. Licensed CC0.

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