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Review
. 2023 Mar 10;24(6):5358.
doi: 10.3390/ijms24065358.

Xerostomia and Its Cellular Targets

Yoon-Jung Kim  1
Affiliations
Review

Xerostomia and Its Cellular Targets

Yoon-Jung Kim. Int J Mol Sci. .

Abstract

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.

Keywords: 1,4,5-trisphosphate receptor; G-protein-coupled receptors; aquaporin 5; intracellular calcium; parasympathetic nerves; store-operated Ca2+ entry; xerostomia.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Neural control of salivation. Stimuli, such as food, smells, and fear, are integrated into the solitary nucleus in the medulla through the afferent pathway. Parasympathetic efferent pathways from the SL and SM glands originate from the facial nerve (VII), and the pathway to the PAR gland originates from the glossopharyngeal nerve (IX). Fluid and electrolyte secretion is activated by the binding of acetylcholine (ACh) to M3 subtype muscarinic ACh receptors (M3 mAChRs). Protein secretion is activated by the binding of norepinephrine (NE) to β adrenergic receptors. cAMP, cyclic adenosine monophosphate; CN, cranial nerve; T1–T3, thoracic segments.
Figure 2
Figure 2
Ca2+ signal transduction and regulation of fluid secretion in salivary gland acinar cells. This figure shows the key signaling events and components involved in the regulation of fluid secretion in salivary gland cells: Fluid is activated by the binding of ACh to subtype M3 mAChRs. Binding activates a GPCR, and the target enzyme is phospholipase C (PLC), which splits phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). IP3 acts by binding to the IP3R on the endoplasmic reticulum (ER) and releasing the Ca2+ stored there. (First step; Ca2+ release from the ER). Stromal interaction molecule–1 (STIM1) in the ER membrane acts as a Ca2+ sensor, causing structural changes when the ER is depleted, and forms store-operated Ca2+ entry (SOCE) with Orai channels or transient receptor canonical (TRPC) channels expressed in the plasma membrane of acinar cells. This leads to an influx of extracellular Ca2+ (second step; Ca2+ influx via the plasma membrane), followed by the translocation of AQP5 at the apical membrane (third step). These increases in [Ca2+]i as a result of neurotransmitter–GPCR binding induce the regulation of ion transport, the production of an osmotic gradient, and the flow of water.
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