Spatial organization of adenylyl cyclase and its impact on dopamine signaling in neurons.

The cAMP cascade is widely recognized to transduce its physiological effects locally through spatially limited cAMP gradients. However, little is known about how the adenylyl cyclase enzymes, which initiate cAMP gradients, are localized. Here we answer this question in physiologically relevant striatal neurons and delineate how AC localization impacts downstream signaling functions. We show that the major striatal AC isoforms are differentially sorted between ciliary and extraciliary domains of the plasma membrane, and that AC9 is uniquely targeted to endosomes. We identify key sorting determinants in the N-terminal cytoplasmic domain responsible for isoform-specific localization. We also 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 show that endosomal localization is critical for AC9 to selectively elevate PKA activity in the nucleus relative to the cytoplasm. These results reveal a precise spatial landscape of the cAMP cascade in neurons and a key role of AC localization in directing downstream signal transduction to the nucleus.