[MARCKS-mediated regulation of exocytotic amylase release: involvement of membrane domain dynamics]

Salivary secretion is essential for maintaining oral and systemic health. In parotid acinar cells, activation of the cAMP-protein kinase A (PKA) pathway following β-adrenergic receptor stimulation triggers the exocytosis of amylase. However, the downstream signaling pathways from PKA activation to exocytotic membrane fusion remain to be fully elucidated. In this review, we focused on Myristoylated alanine-rich C kinase substrate (MARCKS), a major protein kinase C (PKC) substrate, from the perspective of cell membrane homeostasis. Western blot analysis confirmed high MARCKS expression across various exocrine tissues, including the parotid, submandibular, sublingual, and lacrimal glands, as well as the exocrine pancreas. Our results revealed that β-adrenergic receptor stimulation activates PKCδ via PKA, leading to MARCKS phosphorylation in the parotid gland. Phosphorylated MARCKS dissociates from lipid rafts (detergent-resistant membranes) and translocates to the cytosol. Notably, stimulus-induced translocation from lipid rafts was observed in both cAMP-dependent (parotid) and Ca²⁺-dependent (pancreas) secretion. The inhibitory effect of a MARCKS-related peptide (MANS) on amylase secretion suggests that MARCKS functions as a physical or spatial regulator of secretion-related molecules, such as SNARE proteins, on lipid rafts. These findings indicate that MARCKS-mediated membrane domain regulation is a fundamental system underlying exocrine function. This review proposes a novel model of secretion regulated by MARCKS and discusses its pathophysiological significance as a potential therapeutic target for exocrine disorders.