Serotonin 5-HT2C Receptor Cys23Ser Single Nucleotide Polymorphism Associates with Receptor Function and Localization In Vitro

Land, Michelle A.; Chapman, Holly; Davis-Reyes, Brionna D.; Felsing, Daniel E.; Allen, John A.; Moeller, F. Gerard; Elferink, Lisa A.; Cunningham, Kathryn A.; Anastasio, Noelle C.

doi:10.1038/s41598-019-53124-2

Cited by 6 publications

(6 citation statements)

References 79 publications

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“…The 5-HT 2A/2C R antagonist mirtazapine decreased the L-ACC → R-hippocampus EC in tandem with reduced attentional bias for all CUD participants, with outcomes predicated on the HTR2C genotype. Given that cellular studies indicate reduced functionality of the 5-HT 2C R carrying the rs6318 SNP [ 38 , 39 ], the present observations suggest that mirtazapine effectiveness to suppress attentional bias-associated L-ACC → R-hippocampus EC is linked to the degree of 5-HT 2C R functionality. Relatedly, CUD participants with the rs6318 SNP exhibit significantly higher attentional bias toward drug cues relative to carriers of the wild-type gene [ 40 ], and may be more resistant to mirtazapine in the absence of a maximally functional 5-HT 2C R. Although speculative, this line of thought is consistent with observations that describe the interactivity of the 5-HT 2A R and 5-HT 2C R systems in vivo and in vitro (see Introduction) [ 16 , 17 ].…”

Section: Discussionmentioning

confidence: 61%

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A serotonergic biobehavioral signature differentiates cocaine use disorder participants administered mirtazapine

Cunningham

Anastasio

et al. 2022

Transl Psychiatry

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Cocaine use disorder (CUD) patients display heterogenous symptoms and unforeseeable responses to available treatment approaches, highlighting the need to identify objective, accessible biobehavioral signatures to predict clinical trial success in this population. In the present experiments, we employed a task-based behavioral and pharmacogenetic-fMRI approach to address this gap. Craving, an intense desire to take cocaine, can be evoked by exposure to cocaine-associated stimuli which can trigger relapse during attempted recovery. Attentional bias towards cocaine-associated words is linked to enhanced effective connectivity (EC) from the anterior cingulate cortex (ACC) to hippocampus in CUD participants, an observation which was replicated in a new cohort of participants in the present studies. Serotonin regulates attentional bias to cocaine and the serotonergic antagonist mirtazapine decreased activated EC associated with attentional bias, with greater effectiveness in those CUD participants carrying the wild-type 5-HT2CR gene relative to a 5-HT2CR single nucleotide polymorphism (rs6318). These data suggest that the wild-type 5-HT2CR is necessary for the efficacy of mirtazapine to decrease activated EC in CUD participants and that mirtazapine may serve as an abstinence enhancer to mitigate brain substrates of craving in response to cocaine-associated stimuli in participants with this pharmacogenetic descriptor. These results are distinctive in outlining a richer “fingerprint” of the complex neurocircuitry, behavior and pharmacogenetics profile of CUD participants which may provide insight into success of future medications development projects.

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Section: Discussionmentioning

confidence: 61%

“…The single nucleotide polymorphism (SNP) in the 5-HT 2C R gene (rs6318) results in hypofunctional cellular signaling in vitro [ 38 , 39 ]. This SNP also predicts the highest attentional bias toward cocaine-associated stimuli in CUD participants [ 40 ].…”

Section: Introductionmentioning

confidence: 99%

A serotonergic biobehavioral signature differentiates cocaine use disorder participants administered mirtazapine

Cunningham

Anastasio

et al. 2022

Transl Psychiatry

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“…On the other hand, most recently under in vitro conditions with 5-HT promotion, in Ser23 variant cell lines decreased potency and provide peak response intracellular calcium release compared to Cys23 cell lines. In the same study they also detected decreased plasma membrane localization and O-linked glycosylation of 5-HT2CR Ser23 variant so there were distinct functional pharmacological aspects between 5-HT2CR variants (29).…”

Section: Discussion Discussionmentioning

confidence: 70%

Association of the 5HTR2C gene Ser23 variation with childhood allergic asthma

Temel

Ergören

Yilmaz

et al. 2022

The EuroBiotech Journal

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Objective: Allergic asthma is the most frequently observed subtype of individuals with asthma. The effects of serotonin plays in the pathophysiology of asthma has not been clearly determined. Thus, this study aimed to investigate the association between the 5HTR2C gene rs 6318 G>C polymorphism and allergic asthma in pediatric patients in Cyprus. Methods: This study included total number of 177 individuals with 118 control and 59 pediatric patients (43 atopic and 16 non-atopic asthma patient). A skin prick test was performed for each patient to confirm asthma diagnosis and to evaluate atopic status. Genotyping for the 5HTR2C was completed by Real Time-PCR analysis. Results: The genotype distribution frequencies were not in agreement with the Hardy-Weinberg Equilibrium in the patients’ group (p<0.00001). The frequency of the risk allele (allele C) was not significantly different between the patient and control groups (p=0.255). The genotypic distribution between atopic asthma and non-atopic asthma within the patientsts groups was not in agreement with the Hardy-Weinberg Equilibrium (p=0.006). However, risk allele presence showed a statistically significant association with atopy-related asthma (p=0.037). Discussion & Conclusion: Overall, despite the finding of no association between the 5HTR2C rs6318 C allele and childhood asthma, the current results indicated that there is a strong association between the 5HTR2C rs6318 C variant and childhood atopic asthma.

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“…Harvested membranes were centrifuged three times at 4000 x g at 4 °C for 20 minutes and were frozen in -80°C for binding assays. Saturation binding isotherms were performed in 96-well plates using similar methods as previously reported (Land et al, 2019). For saturation binding assays, 0.2 to 16 nM of [ 3 H]SCH23390 (83.2 Ci/mmol, Lot #2551102 PerkinElmer, Waltham, MA) was used to obtain affinity (K d ) and receptor concentration (B max ) values.…”

Section: Methodsmentioning

confidence: 99%

“…x g at 4 ºC for 20 minutes and were frozen in -80°C for binding assays. Saturation binding isotherms were performed in 96-well plates using similar methods as previously reported (Land et al, 2019). For saturation binding assays, 0.2 to 16 nM of…”

Section: Saturation Bindingmentioning

confidence: 99%

Functionally selective dopamine D1 receptor endocytosis and signaling by catechol and non-catechol agonists

Nilson,

Felsing,

Wang

et al. 2024

Preprint

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The dopamine D1 receptor (D1R) has fundamental roles in voluntary movement and memory and is a validated drug target for neurodegenerative and neuropsychiatric disorders. However, previously developed D1R selective agonists possess a catechol moiety which displays poor pharmacokinetic properties. The first selective non-catechol D1R agonists were recently discovered and unexpectedly many of these ligands showed G protein biased signaling. Here, we investigate both catechol and non-catechol D1R agonists to validate potential biased signaling and examine if this impacts agonist-induced D1R endocytosis. We determined that most, but not all, non-catechol agonists display G protein biased signaling at the D1R and have reduced or absent Beta-arrestin recruitment. A notable exception was compound (Cmpd) 19, a non-catechol agonist with full efficacy at both D1R-G protein or D1R Beta-arrestin pathways. In addition, the catechol ligand A-77636 was a highly potent, super agonist for D1R Beta-arrestin activity. When examined for agonist-induced D1R endocytosis, balanced agonists SKF-81297 and Cmpd 19 induced robust D1R endocytosis while the G protein biased agonists did not. The Beta-arrestin super agonist, A-77636, showed significantly increased D1R endocytosis. Moreover, Beta-arrestin recruitment efficacy of tested agonists strongly correlated with total D1R endocytosis. Taken together, these results indicate the degree of D1R signaling functional selectivity profoundly impacts D1R endocytosis regardless of pharmacophore. The range of functional selectivity of these D1R agonists will provide valuable tools to further investigate D1R signaling, trafficking and therapeutic potential.

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Serotonin 5-HT2C Receptor Cys23Ser Single Nucleotide Polymorphism Associates with Receptor Function and Localization In Vitro

Cited by 6 publications

References 79 publications

A serotonergic biobehavioral signature differentiates cocaine use disorder participants administered mirtazapine

A serotonergic biobehavioral signature differentiates cocaine use disorder participants administered mirtazapine

Association of the 5HTR2C gene Ser23 variation with childhood allergic asthma

Functionally selective dopamine D1 receptor endocytosis and signaling by catechol and non-catechol agonists

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