MARCKS phosphorylation and translocation regulate amylase exocytosis in exocrine glands via lipid raft dynamics

Maintaining salivary secretion is crucial for oral and systemic health, yet the complete downstream signaling from cAMP-PKA activation to exocytotic membrane fusion in parotid acinar cells remains unclear. Current understanding points to β-adrenergic receptor stimulation triggering amylase release, but the precise molecular links are elusive. This review focuses on Myristoylated alanine-rich C kinase substrate (MARCKS), a major protein kinase C (PKC) substrate, as a potential mediator of membrane homeostasis during secretion, addressing this critical knowledge gap.

This review synthesized existing literature and presented novel experimental findings on MARCKS's role in exocrine secretion. The authors utilized Western blot analysis to confirm high MARCKS expression across various exocrine tissues, including parotid, submandibular, sublingual, and lacrimal glands, as well as the exocrine pancreas. They investigated the signaling cascade in parotid gland cells following β-adrenergic receptor stimulation, focusing on PKA and PKCδ activation and subsequent MARCKS phosphorylation and translocation dynamics. The study also explored the inhibitory effects of a MARCKS-related peptide (MANS) on amylase secretion.

MARCKS expression was confirmed to be high across multiple exocrine tissues, including the parotid, submandibular, sublingual, and lacrimal glands, and the exocrine pancreas. The review revealed that β-adrenergic receptor stimulation activates PKCδ via PKA, leading to MARCKS phosphorylation in the parotid gland. Phosphorylated MARCKS subsequently dissociates from lipid rafts (detergent-resistant membranes) and translocates to the cytosol. This stimulus-induced translocation from lipid rafts was observed in both cAMP-dependent (parotid) and Ca2+-dependent (pancreas) secretion pathways. The study also demonstrated that a MARCKS-related peptide, MANS, exerted an inhibitory effect on amylase secretion. This suggests that MARCKS acts 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, proposing a novel model of secretion. This mechanism is crucial for understanding how exocrine glands precisely control the release of substances like amylase.