ArticleThe Journal of biological chemistry2011
The antidepressant desipramine is an arrestin-biased ligand at the α(2A)-adrenergic receptor driving receptor down-regulation in vitro and in vivo.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 52 citations in OpenAlex.
- Article
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- Contributions of network structure, chemoarchitecture and diagnostic categories to transitions between cognitive topographies.Nature biomedical engineering · 2024Article
- Adrenoceptor Desensitization: Current Understanding of Mechanisms.Pharmacological reviews · 2024Review
- Dual pancreatic adrenergic and dopaminergic signaling as a therapeutic target of bromocriptine.iScience · 2022Article
- A peptide blocking the ADORA1-neurabin interaction is anticonvulsant and inhibits epilepsy in an Alzheimer's model.JCI insight · 2022Article
- The association ofFrontiers in pharmacology · 2022Article
- Tricyclic antipsychotics promote adipogenic gene expression to potentiate preadipocyte differentiation in vitro.Human cell · 2020Article
- β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade.Science translational medicine · 2020Article
- G-Protein-Coupled Receptors in Heart Disease.Circulation research · 2018Review
- Blockade of α2-adrenergic receptors in prelimbic cortex: impact on cocaine self-administration in adult spontaneously hypertensive rats following adolescent atomoxetine treatment.Psychopharmacology · 2017Article
- The amyloid precursor protein modulates αFASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2017Article
- G Protein-Coupled Receptor Signaling Through β-Arrestin-Dependent Mechanisms.Journal of cardiovascular pharmacology · 2017Review
- The βBritish journal of pharmacology · 2017Article
- Diverse arrestin-recruiting and endocytic profiles of tricyclic antipsychotics acting as direct αNeuropharmacology · 2017Article
- Probing the Molecular Mechanism of Human Soluble Guanylate Cyclase Activation by NO in vitro and in vivo.Scientific reports · 2017Article
- Activation of α2A-adrenergic signal transduction in chondrocytes promotes degenerative remodelling of temporomandibular joint.Scientific reports · 2016Article
- RGS9-2--controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- G protein-coupled receptors in cardiac biology: old and new receptors.Biophysical reviews · 2015Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The neurobiological mechanisms of action underlying antidepressant drugs remain poorly understood. Desipramine (DMI) is an antidepressant classically characterized as an inhibitor of norepinephrine reuptake. Available evidence, however, suggests a mechanism more complex than simple reuptake inhibition. In the present study, we have characterized the direct interaction between DMI and the α(2A)-adrenergic receptor (α(2A)AR), a key regulator of noradrenergic neurotransmission with altered expression and function in depression. DMI alone was found to be sufficient to drive receptor internalization acutely and a robust down-regulation of α(2A)AR expression and signaling following prolonged stimulation in vitro. These effects are achieved through arrestin-biased regulation of the receptor, as DMI selectively induces recruitment of arrestin but not activation of heterotrimeric G proteins. Meanwhile, a physiologically relevant concentration of endogenous agonist (norepinephrine) was unable to sustain a down-regulation response. Prolonged in vivo administration of DMI resulted in significant down-regulation of synaptic α(2A)AR expression, a response that was lost in arrestin3-null animals. We contend that direct DMI-driven arrestin-mediated α(2A)AR down-regulation accounts for the therapeutically desirable but mechanistically unexplained adaptive alterations in receptor expression associated with this antidepressant. Our results provide novel insight into both the pharmacology of this antidepressant drug and the targeting of the α(2A)AR in depression.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.