Local protein kinase A signaling pathologies in the endocrine system

Endocrine signaling relies heavily on the second messenger cAMP to influence different functional outcomes including hormone secretion, steroidogenesis, ion channel regulation, and cell growth. Selectivity of cAMP action is often achieved through compartmentalized activation of protein kinase A (PKA). Local PKA action is organized by A-kinase anchoring proteins. These organellar enzyme scaffolds not only define where and when PKA phosphorylation occurs but also influence which substrates are accessible. A substantial literature suggests that endocrine disease can arise from lesions that promote dysfunctional PKA signaling. Recent studies suggests that common PKA mutations disrupt localization, causing the mutant catalytic subunits to escape A-kinase anchoring protein complexes. Such pathological events are evident in endocrine disorders such as Carney complex, sporadic primary pigmented nodular adrenocortical disease, and adrenal Cushing syndrome where somatic mutations in PKA subunits uncouple normal spatial control of the kinase. We postulate that future therapies should aim to restore the fidelity of local PKA signaling. SIGNIFICANCE STATEMENT: Compartmentalized cAMP signaling, organized by A-kinase anchoring protein scaffolds, is essential for ensuring precise spatial and functional control of endocrine processes. Disruption of this localization by disease-associated protein kinase A mutations uncouples signaling fidelity and drives endocrine pathologies, highlighting restoration of localized protein kinase A activity as a promising therapeutic strategy.