Xerostomia and Its Cellular Targets

Xerostomia, the subjective feeling of a dry mouth associated with dysfunction of the salivary glands, is mainly caused by radiation and chemotherapy, various systemic and autoimmune diseases, and drugs. As saliva plays numerous essential roles in oral and systemic health, xerostomia significantly reduces quality of life, but its prevalence is increasing. Salivation mainly depends on parasympathetic and sympathetic nerves, and the salivary glands responsible for this secretion move fluid unidirectionally through structural features such as the polarity of acinar cells. Saliva secretion is initiated by the binding of released neurotransmitters from nerves to specific G-protein-coupled receptors (GPCRs) on acinar cells. This signal induces two intracellular calcium (Ca²⁺) pathways (Ca²⁺ release from the endoplasmic reticulum and Ca²⁺ influx across the plasma membrane), and this increased intracellular Ca²⁺ concentration ([Ca²⁺]_i) causes the translocation of the water channel aquaporin 5 (AQP5) to the apical membrane. Consequently, the GPCR-mediated increased [Ca²⁺]_i in acinar cells promotes saliva secretion, and this saliva moves into the oral cavity through the ducts. In this review, we seek to elucidate the potential of GPCRs, the inositol 1,4,5-trisphosphate receptor (IP₃R), store-operated Ca²⁺ entry (SOCE), and AQP5, which are essential for salivation, as cellular targets in the etiology of xerostomia.