Airway smooth muscle prostaglandin-EP1 receptors directly modulate β2-adrenergic receptors within a unique heterodimeric complex
Airway smooth muscle prostaglandin-EP1 receptors directly modulate β2-adrenergic receptors within a unique heterodimeric complex
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DOI：
10.1172/jci25840
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发表时间：
2006-05-01
影响因子：
15.9
通讯作者：
Liggett, SB
中科院分区：
文献类型：
--
作者：
McGraw, DW;Mihlbachler, KA;Liggett, SB
气道平滑肌（ASM） 7跨膜受体在哮喘期间激活，或通过支气管扩张剂如β(2)-肾上腺素能受体（PAR）激动剂治疗，多重和矛盾的作用表明广泛的受体互扰。我们研究了前列腺素- ep1受体的信号传导，因为其内源性激动剂前列腺素E-2在气道中含量丰富，但其功能含义尚不明确。EP1的激活不能通过G（α q）偶联受体引起小鼠气管的ASM收缩。然而，EP1的激活显著降低了PAR激动剂的支气管扩张功能，但没有降低福斯克林，表明早期途径相互作用。EP1的激活降低了ASM中PAR刺激的cAMP，但不促进或增强PAR磷酸化或改变PAR转运。生物发光共振能量转移显示EP1与β (2)AR形成异源二聚体，经EP1激动剂修饰后形成异源二聚体。在细胞膜[S-35]GTP γ S结合研究中，二聚体中EP1组分的存在使PAR与Gus分离，EP1激动剂的激活强化了这一作用。因此，EP1似乎对气道张力没有显著的直接影响，但作为PAR的调节剂，通过EP1: β (2)AR异二聚体信号复合物施加的空间相互作用改变Gus偶联，最终影响PAR介导的支气管舒张。这一机制可能有助于哮喘中发现的-受体激动剂耐药性。
Multiple and paradoxical effects of airway smooth muscle (ASM) 7-transmembrane-spanning receptors activated during asthma, or by treatment with bronchodilators such as beta(2)-adrenergic receptor (PAR) agonists, indicate extensive receptor crosstalk. We examined the signaling of the prostanoid-EP1 receptor, since its endogenous agonist prostaglandin E-2 is abundant in the airway, but its functional implications are poorly defined. Activation of EP1 failed to elicit ASM contraction in mouse trachea via this G(alpha q)-coupled receptor. However, EP1 activation markedly reduced the bronchodilatory function Of PAR agonist, but not forskolin, indicating an early pathway interaction. Activation of EP1 reduced PAR-stimulated cAMP in ASM but did not promote or augment PAR phosphorylation or alter PAR trafficking. Bioluminescence resonant energy transfer showed EP1 and beta(2)AR formed heterodimers, which were further modified by EP1 agonist. In cell membrane [S-35]GTP gamma S binding studies, the presence of the EP1 component of the dimer uncoupled PAR from Gus, an effect accentuated by EP1 agonist activation. Thus alone, EP1 does not appear to have a significant direct effect on airway tone but acts as a modulator of the PAR, altering Gus coupling via steric interactions imposed by the EP1:beta(2)AR heterodimeric signaling complex and ultimately affecting PAR-mediated bronchial relaxation. This mechanism may contribute to beta-agonist resistance found in asthma.