Paper
The Antidepressant Desipramine Is an Arrestin-biased Ligand at the α2A-Adrenergic Receptor Driving Receptor Down-regulation in Vitro and in Vivo*
Published Aug 22, 2011 · C. Cottingham, Yunjia Chen, K. Jiao
The Journal of Biological Chemistry
49
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3
Influential Citations
Abstract
Background: Antidepressant drugs have complex and poorly understood mechanisms of action potentially involving G protein-coupled receptors. Results: Desipramine binds the α2A-adrenergic receptor, leading to arrestin recruitment and trafficking responses but not signaling. Conclusion: Desipramine directly drives down-regulation of neuronal α2A-adrenergic receptors in an arrestin3-dependent fashion. Significance: Arrestin-biased targeting of G protein-coupled receptors may represent a novel therapeutic strategy in the neuropharmacology of depressive disorders. 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 α2A-adrenergic receptor (α2AAR), 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 α2AAR 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 α2AAR expression, a response that was lost in arrestin3-null animals. We contend that direct DMI-driven arrestin-mediated α2AAR 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 α2AAR in depression.
In Vitro StudyDesipramine directly drives down-regulation of neuronal 2A-adrenergic receptors in an arrestin3-dependent manner, providing a novel therapeutic strategy for depressive disorders.
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