RNA Editing of Serotonin 2C Receptor and Alcohol Intake

Abstract

Serotonin 2C receptor (5-HT 2C R) belongs to the superfamily of seven transmembrane domain receptors coupled to G proteins (GPCR). It is broadly distributed in the CNS and its expression is relatively high in the limbic system including the amygdala, nucleus accumbens (NAc), hippocampus, and hypothalamus. Based on its expression patterns and numerous pharmacological studies, 5-HT 2C R is thought to be involved in various brain functions including emotion, appetite, and motor behavior. Here, we review 5-HT 2C R and its relationship with alcohol intake with a particular focus on the involvement of 5-HT 2C R mRNA editing and its association with alcohol preference in mice. RNA editing is a post-transcriptional modification mechanism. In mammals, adenosine is converted to inosine by the deamination enzymes ADAR1 and ADAR2. 5-HT 2C R is the only GPCR subjected to RNA editing within the coding region. It has five editing sites in exon 5 that encode the second intracellular loop. Consequently, three amino acids residues (I156, N158, and I160) of the unedited receptor (INI) may be altered to differently edited isoforms, resulting in a change of receptor activity such as 5-HT potency and G-protein coupling. 5-HT 2C R in the NAc is involved in enhanced alcohol drinking after chronic alcohol exposure and alterations in 5-HT 2C R mRNA editing is important in determining the alcohol preference using different strains of mice and genetically modified mice. RNA editing of this receptor may participate in the development of alcoholism.

Alcohol Dependence and Withdrawal Impair Serotonergic Regulation of GABA Transmission in the Rat Central Nucleus of the Amygdala

“…Additionally, it is well accepted that mRNA levels do not necessarily reflect levels of translated protein, and protein localization and activity may also impact function/signaling without altering mRNA levels. Furthermore, there is growing evidence that Htr2c undergoes RNA editing in neuropsychiatric disease, such as PTSD (Baratta et al, 2016), and such Htr2c alternative splicing can cause the resulting 5-HT2C isoform to be constitutively active in the absence of ligands (Tanaka and Watanabe, 2019). Chronic ethanol vapor exposure in mice (C57BL6) also increases levels of edited isoforms of Htr2c mRNA (Watanabe et al, 2014) in the nucleus accumbens, which is associated with increased ethanol drinking.…”

Biomarkers of Affective Dysregulation Associated with In Utero Exposure to EtOH

“…In the ventral hippocampus, HTR1A, 2A, 2C, and 7 play a role in mood- and anxiety-related behavior and are involved in the antidepressant effects of SSRIs. Expression of the 5-HT2C receptor in mice modulated alcohol intake, which may be relevant to human alcoholism [ 103 ]. Increased cortical expression of 5-HT2CR mRNA had previously been found in major depressive suicide victims [ 104 ].…”

RNA Editing: A New Therapeutic Target in Amyotrophic Lateral Sclerosis and Other Neurological Diseases

“…Comprehensive studies on alterations in RNA editing have demonstrated changes in editing efficiencies at many editing sites in the brains of patients with autism spectrum disorder, a common neurodevelopmental disorder characterized by social communication deficits and repetitive sensorimotor behaviors [102]; however, no specific editing site relevant to the pathogenesis could be identified [69,103]. In addition, studies in mice and rats have shown negative effects of alcohol and/or cocaine abuse/abstinence on the RNA editing efficiency of ADAR2 [104,105].…”