Cardiomyocyte b₃-adrenoceptors (b₃-ARs) coupled to soluble guanylyl cyclase (sGC)-dependent production of the second messenger 3',5'-cyclic guanosine monophosphate (cGMP) have been shown to protect from heart failure. However, the exact localization of these receptors to fine membrane structures and subcellular compartmentation of b₃-AR/cGMP signals underpinning this protection in health and disease remain elusive. Here, we used a Förster Resonance Energy Transfer (FRET)-based cGMP biosensor combined with scanning ion conductance microscopy (SICM) to show that functional β₃-ARs are mostly confined to the T-tubules of healthy rat cardiomyocytes. Heart failure, induced via myocardial infarction, causes a decrease of the cGMP levels generated by these receptors and a change of subcellular cGMP compartmentation. Furthermore, attenuated cGMP signals led to impaired phosphodiesterase 2 dependent negative cGMP-to-cAMP cross-talk. In conclusion, topographic and functional reorganization of the b₃-AR/cGMP signalosome happens in heart failure and should be considered when designing new therapies acting via this receptor.

中文翻译：

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β3-肾上腺素受体的重新分布削弱了衰竭心肌细胞中的NO / cGMP / PDE2信号传导

心肌细胞b _3-肾上腺素能受体（b ₃ -ARs）与可溶性鸟苷基环化酶（sGC）依赖的第二信使3'，5'-环鸟苷单磷酸酯（cGMP）的产生相关联，可预防心力衰竭。然而，这些受体在b ₃ -AR / cGMP信号的精细膜结构和亚细胞区隔中的确切定位仍然是健康和疾病保护的基础。在这里，我们使用了一个共振能量转移（FRET）的cGMP的生物传感器结合扫描离子电导显微镜（SICM）以表明功能性β ₃-ARs主要局限于健康大鼠心肌细胞的T管。通过心肌梗塞诱发的心力衰竭会导致这些受体产生的cGMP水平降低，并改变亚细胞cGMP间隔。此外，衰减的cGMP信号导致磷酸二酯酶2依赖性负cGMP与cAMP的串扰减弱。总之，b ₃ -AR / cGMP信号小体的形貌和功能重组在心力衰竭中发生，在设计通过该受体发挥作用的新疗法时应予以考虑。