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β-Adrenergic receptor structure and function: molecular insights guiding the development of novel therapeutic
Michael G Z Ghali1,2,3,4,5,6, Ulf P Arborelius1,2, M Gazi Yaşargil6
1Department of Neurological Surgery, Karolinska Institutet, Stockholm, Sweden.
Abstract:
β adrenergic receptors mediate effects via activation of G proteins, transactivation of membrane growth factor receptors, or β adrenergic receptor-β arrestin-facilitated scaffold-mediated signaling. Agonist occupancy of the β adrenergic receptor induces desensitization by promoting β adrenergic receptor kinase phosphorylation of the carboxyl terminal domain, facilitating binding of the amino terminal of the β arrestin, which sterically inhibits interactions between β adrenergic receptors and G proteins and induces clathrin-coated pit-mediated receptor endocytosis. Scaffold formation promoted by β arrestin binding to the β adrenergic receptor activates extracellular regulated kinase 1/2 in a manner which elicits cytosolic retention of, and prevents promotion of nuclear transcriptional activity by, mitogen-activated protein kinase. The β adrenergic receptor kinase also interacts with a yet to be determined microsomal membrane protein via high-affinity electrostatic interactions. We evaluate β adrenergic receptor structure, function, and downstream signaling and β arrestin-mediated desensitization, receptor endocytosis, and scaffold-facilitated signal transduction in order to illumine therapeutic strategies designed to modulate these pathways. We trust these approaches may arm us with the capacity to selectively modulate signal transduction pathways regulating cellular proliferation, immunogenicity, angiogenesis, and invasive and metastatic potential implicated in cancer initiation, promotion, and progression.
Insights
Beta adrenergic receptors (β adrenergic receptors) signal through G proteins or arrestin scaffolds. Arrestin binding causes receptor desensitization and endocytosis, impacting cancer progression pathways.
Area of Science:
- Cellular signaling pathways
- Molecular pharmacology
- Cancer biology
Background:
- Beta adrenergic receptors (β adrenergic receptors) mediate cellular responses via G protein activation, growth factor receptor transactivation, or β-arrestin-mediated scaffolding.
- Agonist binding leads to β adrenergic receptor kinase (βARK) phosphorylation, promoting β-arrestin interaction, G protein inhibition, and receptor endocytosis.
- β-arrestin scaffolding activates extracellular regulated kinase 1/2 (ERK1/2), influencing mitogen-activated protein kinase (MAPK) localization and activity.
Purpose of the Study:
- To elucidate the structure, function, and downstream signaling of β adrenergic receptors.
- To investigate β-arrestin-mediated desensitization, receptor endocytosis, and scaffold-facilitated signal transduction.
- To identify therapeutic strategies for modulating β adrenergic receptor pathways in cancer.
Main Methods:
- Evaluation of β adrenergic receptor structure and function.
- Analysis of downstream signaling pathways, including G protein and β-arrestin interactions.
- Assessment of β-arrestin-mediated desensitization and receptor endocytosis mechanisms.
- Investigation of scaffold-facilitated signal transduction pathways.
Main Results:
- β adrenergic receptor activation involves multiple signaling routes, including G proteins and β-arrestin scaffolds.
- β-arrestin binding induces receptor desensitization and endocytosis by inhibiting G protein coupling.
- Scaffold formation by β-arrestin modulates MAPK signaling, affecting cellular processes.
- βARK interacts with unknown microsomal membrane proteins via electrostatic interactions.
Conclusions:
- Understanding β adrenergic receptor signaling and β-arrestin interactions is crucial for therapeutic development.
- Modulating these pathways offers potential for targeting cancer cell proliferation, immunogenicity, angiogenesis, and metastasis.
- Selective modulation of signal transduction pathways can impact cancer initiation, promotion, and progression.
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