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Structural basis of agonist specificity of α_1A-adrenergic receptor.

ABSTRACT: α₁-adrenergic receptors (α₁-ARs) play critical roles in the cardiovascular and nervous systems where they regulate blood pressure, cognition, and metabolism. However, the lack of specific agonists for all α₁ subtypes has limited our understanding of the physiological roles of different α₁-AR subtypes, and led to the stagnancy in agonist-based drug development for these receptors. Here we report cryo-EM structures of α_1A-AR in complex with heterotrimeric G-proteins and either the endogenous common agonist epinephrine or the α_1A-AR-specific synthetic agonist A61603. These structures provide molecular insights into the mechanisms underlying the discrimination between α_1A-AR and α_1B-AR by A61603. Guided by the structures and corresponding molecular dynamics simulations, we engineer α_1A-AR mutants that are not responsive to A61603, and α_1B-AR mutants that can be potently activated by A61603. Together, these findings advance our understanding of the agonist specificity for α₁-ARs at the molecular level, opening the possibility of rational design of subtype-specific agonists.

SUBMITTER: Su M

PROVIDER: S-EPMC10415349 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Structural basis of agonist specificity of α1A-adrenergic receptor.

Su Minfei M Wang Jinan J Xiang Guoqing G Do Hung Nguyen HN Levitz Joshua J Miao Yinglong Y Huang Xin-Yun XY

Nature communications 20230810 1

α1-adrenergic receptors (α1-ARs) play critical roles in the cardiovascular and nervous systems where they regulate blood pressure, cognition, and metabolism. However, the lack of specific agonists for all α1 subtypes has limited our understanding of the physiological roles of different α1-AR subtypes, and led to the stagnancy in agonist-based drug development for these receptors. Here we report cryo-EM structures of α1A-AR in complex with he ...[more]

PMID: 37563160

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Project description:Chronic stimulation of cardiac α1A-adrenergic receptors (α1A-ARs) improves symptoms in multiple preclinical models of heart failure. However, the translational significance remains unclear. Human engineered heart tissues (EHTs) provide a means of quantifying the effects of chronic α1A-AR stimulation on human cardiomyocyte physiology. EHTs were created from thin slices of decellularized pig myocardium seeded with human induced pluripotent stem cell (iPSC)-derived cardiomyocytes and fibroblasts. With a paired experimental design, EHTs were cultured for 3 wk, mechanically tested, cultured again for 2 wk with α1A-AR agonist A61603 (10 nM) or vehicle control, and retested after drug washout for 24 h. Separate control experiments determined the effects of EHT age (3-5 wk) or repeat mechanical testing. We found that chronic A61603 treatment caused a 25% increase of length-dependent activation (LDA) of contraction compared with vehicle treatment (n = 7/group, P = 0.035). EHT force was not increased after chronic A61603 treatment. However, after vehicle treatment, EHT force was increased by 35% relative to baseline testing (n = 7/group, P = 0.022), suggesting EHT maturation. Control experiments suggested that increased EHT force resulted from repeat mechanical testing, not from EHT aging. RNA-seq analysis confirmed that the α1A-AR is expressed in human EHTs and found chronic A61603 treatment affected gene expression in biological pathways known to be activated by α1A-ARs, including the MAP kinase signaling pathway. In conclusion, increased LDA in human EHT after chronic A61603 treatment raises the possibility that chronic stimulation of the α1A-AR might be beneficial for increasing LDA in human myocardium and might be beneficial for treating human heart failure by restoring LDA.NEW & NOTEWORTHY Chronic stimulation of α1A-adrenergic receptors (α1A-ARs) is known to mediate therapeutic effects in animal heart failure models. To investigate the effects of chronic α1A-AR stimulation in human cardiomyocytes, we tested engineered heart tissue (EHT) created with iPSC-derived cardiomyocytes. RNA-seq analysis confirmed human EHT expressed α1A-ARs. Chronic (2 wk) α1A-AR stimulation with A61603 (10 nM) increased length-dependent activation (LDA) of contraction. Chronic α1A-AR stimulation might be beneficial for treating human heart failure by restoring LDA.

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Structural basis of agonist specificity of α_1A-adrenergic receptor.

Publications

Structural basis of agonist specificity of α<sub>1A</sub>-adrenergic receptor.

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