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Alem W Kahsai

Assistant Professor in Medicine
Medicine, Cardiology

Selected Publications


Role of the V2R-βarrestin-Gβγ complex in promoting G protein translocation to endosomes.

Journal Article Commun Biol · July 7, 2024 Classically, G protein-coupled receptors (GPCRs) promote signaling at the plasma membrane through activation of heterotrimeric Gαβγ proteins, followed by the recruitment of GPCR kinases and βarrestin (βarr) to initiate receptor desensitization and internal ... Full text Link to item Cite

Signal transduction at GPCRs: Allosteric activation of the ERK MAPK by β-arrestin.

Journal Article Proc Natl Acad Sci U S A · October 24, 2023 β-arrestins are multivalent adaptor proteins that bind active phosphorylated G protein-coupled receptors (GPCRs) to inhibit G protein signaling, mediate receptor internalization, and initiate alternative signaling events. β-arrestins link agonist-stimulate ... Full text Link to item Cite

Allosteric modulator potentiates β2AR agonist-promoted bronchoprotection in asthma models.

Journal Article J Clin Invest · September 15, 2023 Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled β2-adrenergic receptor (β2AR) agonists (β2-agonists) promote - with limited efficacy - bronchodilation in asthma. All β2-agonists are canonical orthosteric ligands ... Full text Link to item Cite

GPCR-mediated β-arrestin activation deconvoluted with single-molecule precision.

Journal Article Cell · May 12, 2022 β-arrestins bind G protein-coupled receptors to terminate G protein signaling and to facilitate other downstream signaling pathways. Using single-molecule fluorescence resonance energy transfer imaging, we show that β-arrestin is strongly autoinhibited in ... Full text Link to item Cite

β-Arrestin-Biased Allosteric Modulator Potentiates Carvedilol-Stimulated β Adrenergic Receptor Cardioprotection.

Journal Article Mol Pharmacol · December 2021 β 1 adrenergic receptors (β 1ARs) are central regulators of cardiac function and a drug target for cardiac disease. As a member of the G protein-coupled receptor family, β 1ARs activate cellular signaling by primarily coupling to Gs proteins to activate ad ... Full text Link to item Cite

The GPCR-β-arrestin complex allosterically activates C-Raf by binding its amino terminus.

Journal Article J Biol Chem · December 2021 G protein-coupled receptors (GPCRs) convert external stimuli into cellular signals through heterotrimeric guanine nucleotide-binding proteins (G-proteins) and β-arrestins (βarrs). In a βarr-dependent signaling pathway, βarrs link GPCRs to various downstrea ... Full text Link to item Cite

Unique Positive Cooperativity Between the β-Arrestin-Biased β-Blocker Carvedilol and a Small Molecule Positive Allosteric Modulator of the β2-Adrenergic Receptor.

Journal Article Mol Pharmacol · November 2021 Among β-blockers that are clinically prescribed for heart failure, carvedilol is a first-choice agent with unique pharmacological properties. Carvedilol is distinct from other β-blockers in its ability to elicit β-arrestin-biased agonism, which has been su ... Full text Link to item Cite

Noncanonical scaffolding of Gαi and β-arrestin by G protein-coupled receptors.

Journal Article Science · March 12, 2021 Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) are common drug targets and canonically couple to specific Gα protein subtypes and β-arrestin adaptor proteins. G protein-mediated signaling and β-arrestin-mediated sig ... Full text Link to item Cite

DeSiphering receptor core-induced and ligand-dependent conformational changes in arrestin via genetic encoded trimethylsilyl 1H-NMR probe.

Journal Article Nat Commun · September 25, 2020 Characterization of the dynamic conformational changes in membrane protein signaling complexes by nuclear magnetic resonance (NMR) spectroscopy remains challenging. Here we report the site-specific incorporation of 4-trimethylsilyl phenylalanine (TMSiPhe) ... Full text Link to item Cite

Mechanism of β2AR regulation by an intracellular positive allosteric modulator.

Journal Article Science · June 28, 2019 Drugs targeting the orthosteric, primary binding site of G protein-coupled receptors are the most common therapeutics. Allosteric binding sites, elsewhere on the receptors, are less well-defined, and so less exploited clinically. We report the crystal stru ... Full text Link to item Cite

Small-Molecule Positive Allosteric Modulators of the β2-Adrenoceptor Isolated from DNA-Encoded Libraries.

Journal Article Mol Pharmacol · August 2018 Conventional drug discovery efforts at the β2-adrenoceptor (β2AR) have led to the development of ligands that bind almost exclusively to the receptor's hormone-binding orthosteric site. However, targeting the largely unexplored and evolutionarily unique al ... Full text Link to item Cite

Design, synthesis, and functional assessment of Cmpd-15 derivatives as negative allosteric modulators for the β2-adrenergic receptor.

Journal Article Bioorg Med Chem · May 15, 2018 The β2-adrenergic receptor (β2AR), a G protein-coupled receptor, is an important therapeutic target. We recently described Cmpd-15, the first small molecule negative allosteric modulator (NAM) for the β2AR. Herein we report in details the design, synthesis ... Full text Link to item Cite

Gq activity- and β-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are required for male fertility.

Journal Article Elife · February 2, 2018 Luminal fluid reabsorption plays a fundamental role in male fertility. We demonstrated that the ubiquitous GPCR signaling proteins Gq and β-arrestin-1 are essential for fluid reabsorption because they mediate coupling between an orphan receptor ADGRG2 (GPR ... Full text Link to item Cite

Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure.

Journal Article Nature · August 24, 2017 G-protein-coupled receptors (GPCRs) pose challenges for drug discovery efforts because of the high degree of structural homology in the orthosteric pocket, particularly for GPCRs within a single subfamily, such as the nine adrenergic receptors. Allosteric ... Full text Link to item Cite

Adaptive Activation of a Stress Response Pathway Improves Learning and Memory Through Gs and β-Arrestin-1-Regulated Lactate Metabolism.

Journal Article Biol Psychiatry · April 15, 2017 BACKGROUND: Stress is a conserved physiological response in mammals. Whereas moderate stress strengthens memory to improve reactions to previously experienced difficult situations, too much stress is harmful. METHODS: We used specific β-adrenergic agonists ... Full text Link to item Cite