Faculty, Staff and Student Publications
Publication Date
9-27-2024
Journal
Nature Communications
Abstract
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.
Keywords
Adenylyl Cyclases, Animals, Signal Transduction, Dopamine, Neurons, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Endosomes, Cell Membrane, Mice, Corpus Striatum, Receptors, Dopamine, Golgi Apparatus, Cell Nucleus, Humans, HEK293 Cells, Cell signalling, Membranes, Endosomes, Endosomes, Cellular neuroscience
DOI
10.1038/s41467-024-52575-0
PMID
39333071
PMCID
PMC11436756
PubMedCentral® Posted Date
9-27-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes