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Article
Open AccessEstablishment of multi-stage intravenous self-administration paradigms in mice
Genetically tractable animal models provide needed strategies to resolve the biological basis of drug addiction. Intravenous self-administration (IVSA) is the gold standard for modeling psychostimulant and opi...
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Article
Open AccessA cancer rainbow mouse for visualizing the functional genomics of oncogenic clonal expansion
Field cancerization is a premalignant process marked by clones of oncogenic mutations spreading through the epithelium. The timescales of intestinal field cancerization can be variable and the mechanisms drivi...
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Article
Slow-release delivery enhances the pharmacological properties of oral 5-hydroxytryptophan: mouse proof-of-concept
5-hydroxytryptophan (5-HTP) has shown therapeutic promise in a range of human CNS disorders. But native 5-HTP immediate release (IR) is poorly druggable, as rapid absorption causes rapid onset of adverse event...
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Article
Open AccessAdipocyte β-arrestin-2 is essential for maintaining whole body glucose and energy homeostasis
β-Arrestins are major regulators of G protein-coupled receptor-mediated signaling processes. Their potential roles in regulating adipocyte function in vivo remain unexplored. Here we report the novel finding t...
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Protocol
A Brief History of the β-Arrestins
Arrestins have now been implicated in the actions of virtually every G protein-coupled receptor (GPCR) for which they have been examined. Originally discovered for their role in the turnoff of visual perceptio...
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Article
Engineered D2R Variants Reveal the Balanced and Biased Contributions of G-Protein and β-Arrestin to Dopamine-Dependent Functions
The dopamine D2 receptor (D2R), like many G-protein-coupled receptors, signals through G-protein- and β-arrestin-dependent pathways. Preferential activation of one of these pathways is termed functional selectivi...
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Article
Open Accessβ-arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions
β-arrestins are critical signalling molecules that regulate many fundamental physiological functions including the maintenance of euglycemia and peripheral insulin sensitivity. Here we show that inactivation o...
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Article
SSRI Augmentation by 5-Hydroxytryptophan Slow Release: Mouse Pharmacodynamic Proof of Concept
Drugs, notably SSRIs, that elevate brain extracellular 5-HT (5-HTExt) are antidepressants. Unfortunately, most patients fail to remit. Multipronged clinical evidence suggests that elevating 5-HTExt beyond the SSR...
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Article
Antidepressants at work
Structures of the serotonin transporter protein SERT in complex with two different antidepressants shed light on how these drugs act, and point to possible targets for future drug development. See Article ...
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Article
Effects of β-Arrestin-Biased Dopamine D2 Receptor Ligands on Schizophrenia-Like Behavior in Hypoglutamatergic Mice
Current antipsychotic drugs (APDs) show efficacy with positive symptoms, but are limited in treating negative or cognitive features of schizophrenia. Whereas all currently FDA-approved medications target prima...
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Article
Open AccessA rapid and affordable screening platform for membrane protein trafficking
Membrane proteins regulate a diversity of physiological processes and are the most successful class of targets in drug discovery. However, the number of targets adequately explored in chemical space and the li...
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Article
The interaction of escitalopram and R-citalopram at the human serotonin transporter investigated in the mouse
Escitalopram appears to be a superior antidepressant to racemic citalopram. It has been hypothesized that binding of R-citalopram to the serotonin transporter (SERT) antagonizes escitalopram binding to and inh...
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Article
Selective Deletion of GRK2 Alters Psychostimulant-Induced Behaviors and Dopamine Neurotransmission
GRK2 is a G protein-coupled receptor kinase (GRK) that is broadly expressed and is known to regulate diverse types of receptors. GRK2 null animals exhibit embryonic lethality due to a severe developmental hear...
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Article
Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs
The Smoothened receptor (SMO) mediates signal transduction in the hedgehog pathway, which is implicated in normal development and carcinogenesis. SMO antagonists can suppress the growth of some tumours; howeve...
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Article
Methylphenidate amplifies the potency and reinforcing effects of amphetamines by increasing dopamine transporter expression
Methylphenidate (MPH) is commonly diverted for recreational use, but the neurobiological consequences of exposure to MPH at high, abused doses are not well defined. Here we show that MPH self-administration in...
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Article
A Gαs DREADD Mouse for Selective Modulation of cAMP Production in Striatopallidal Neurons
Here, we describe a newly generated transgenic mouse in which the Gs DREADD (rM3Ds), an engineered G protein-coupled receptor, is selectively expressed in striatopallidal medium spiny neurons (MSNs). We first ...
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Article
Open AccessThe role of GRK6 in animal models of Parkinson's Disease and L-DOPA treatment
G protein-coupled Receptor Kinase 6 (GRK6) belongs to a family of kinases that phosphorylate GPCRs. GRK6 levels were found to be altered in Parkinson's Disease (PD) and D2 dopamine receptors are supersensitive in...
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Article
A Dopamine D1 Receptor-Dependent β-Arrestin Signaling Complex Potentially Regulates Morphine-Induced Psychomotor Activation but not Reward in Mice
Morphine is a widely used analgesic in humans that is associated with multiple untoward effects, such as addiction and physical dependence. In rodent models, morphine also induces locomotor activity. These eff...
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Article
Open AccessNorepinephrine transport-mediated gene expression in noradrenergic neurogenesis
We have identified a differential gene expression profile in neural crest stem cells that is due to deletion of the norepinephrine transporter (NET) gene. NET is the target of psychotropic substances, such as ...
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Article
Building a new conceptual framework for receptor heteromers
Receptor heteromers constitute a new area of research that is resha** our thinking about biochemistry, cell biology, pharmacology and drug discovery. In this commentary, we recommend clear definitions that s...
