Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA.
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
Nat Commun. 2024 Sep 27;15(1):8297. doi: 10.1038/s41467-024-52575-0.
The cAMP cascade is increasingly recognized to transduce physiological effects locally through spatially limited cAMP gradients. However, little is known about how adenylyl cyclase enzymes that initiate cAMP gradients are localized. Here we address this question in physiologically relevant striatal neurons and investigate how AC localization impacts downstream signaling function. We show that the major striatal AC isoforms are differentially sorted between ciliary and extraciliary domains of the plasma membrane, and that one isoform, AC9, is uniquely concentrated in endosomes. We identify key sorting determinants in the N-terminal cytoplasmic domain responsible for isoform-specific localization. We further show that AC9-containing endosomes accumulate activated dopamine receptors and form an elaborately intertwined network with juxtanuclear PKA stores bound to Golgi membranes. Finally, we provide evidence that endosomal localization enables AC9 to selectively elevate PKA activity in the nucleus relative to the cytoplasm. Together, these results reveal a precise spatial landscape of the cAMP cascade in neurons and a key role of AC localization in directing downstream PKA signaling to the nucleus.
cAMP 级联反应越来越被认为通过空间限制的 cAMP 梯度在局部转导生理效应。然而，对于起始 cAMP 梯度的腺苷酸环化酶酶如何定位，人们知之甚少。本文中，我们在生理相关的纹状体神经元中解决了这个问题，并研究了 AC 定位如何影响下游信号转导功能。结果显示，主要的纹状体 AC 同工型在质膜的纤毛和细胞外区室之间存在差异分拣，并且一种同工型 AC9 特异性地集中在内涵体中。我们确定了负责同工型特异性定位的 N 端细胞质结构域中的关键分拣决定因素。我们进一步表明，含有 AC9 的内涵体积累激活的多巴胺受体，并与结合到高尔基膜的核周 PKA 库形成错综复杂的交织网络。最后，我们提供了证据表明内涵体定位使 AC9 能够相对于细胞质选择性地升高核内的 PKA 活性。总之，这些结果揭示了神经元中 cAMP 级联反应的精确空间景观，以及 AC 定位在将下游 PKA 信号导向核内方面的关键作用。
