A localized cAMP–Ca2+ signaling network in rat parotid acinar cells driven by the TAAR1 agonist RO5256390

Abstract

Trace amine–associated receptor 1 (TAAR1) is highly expressed in rat parotid acinar cells; however, its role in exocrine Ca2+ signaling remains unclear. We herein demonstrated that the selective TAAR1 agonist RO5256390 induced rapid and transient increases in intracellular Ca2+ levels that were completely abolished by the TAAR1 antagonist EPPTB, confirming receptor specificity. Pharmacological dissection revealed dual contributions from extracellular Ca2+ influx via L‐type, T‐type, and receptor‐operated channels and Ca2+ release from intracellular stores mediated by phospholipase C, inositol trisphosphate receptors, and ryanodine receptors. Inhibition of adenylyl cyclase or protein kinase A (PKA) nearly abolished the Ca2+ response, and displacement of PKA from AKAPs using the cell‐permeable AKAP‐displacing peptide st‐Ht31 produced a comparable suppression, underscoring the requirement for microdomain‐restricted PKA activity. Exchange protein directly activated by cAMP 2 (Epac 2) and downstream calmodulin‐dependent protein kinase II were also indispensable, whereas Epac 1 was dispensable. The present study identified a TAAR1‐centered, 3’,5’‐cyclic adenosine monophosphate microdomain network that co‐ordinates Ca2+ entry and release, thereby providing novel targets for the modulation of salivary secretion.