Next Article in Journal
Analysis of the Electron Density of a Water Molecule Encapsulated by Two Cholic Acid Residues
Next Article in Special Issue
A Catalog of Coding Sequence Variations in Salivary Proteins’ Genes Occurring during Recent Human Evolution
Previous Article in Journal
Endocrine-Disrupting Chemicals and Disease Endpoints
Previous Article in Special Issue
Peroxisomes Are Highly Abundant and Heterogeneous in Human Parotid Glands
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 24
Issue 6
10.3390/ijms24065358
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Xerostomia and Its Cellular Targets

by
Yoon-Jung Kim
Department of Physiology and Neuroscience, Dental Research Institute, Seoul National University School of Dentistry, Seoul 03080, Republic of Korea
Int. J. Mol. Sci. 2023, 24(6), 5358; https://doi.org/10.3390/ijms24065358
Submission received: 31 December 2022 / Revised: 26 February 2023 / Accepted: 2 March 2023 / Published: 10 March 2023
(This article belongs to the Special Issue Recent Advances in Salivary Gland and Their Function 2.0)
Browse Figures
Versions Notes

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.

1. Introduction

Saliva is essential for maintaining a healthy oral environment and overall health. The salivary glands regulate salivation according to the surrounding environment and circumstances, and various factors can affect the volume and composition of saliva. Xerostomia (dry mouth), defined as a subjective feeling of oral dryness [1], is a term derived from the Greek “xeros” (ξηρός), meaning “dry”, and “stoma” (στόμα), meaning “mouth”. Xerostomia results in decreased salivary flow and changes in the composition of saliva. This condition has various causes and is affected by the function of the salivary glands. However, a dry sensation in the mouth can also be observed in individuals with normal salivary gland function [2,3]. The main causes of xerostomia are aging, radiation to the head and neck, and Sjögren’s syndrome; however, the most common cause is drug-induced xerostomia, which is associated with more than 400 different drugs. Xerostomia decreases normal saliva function, which increases the occurrence of bad breath, dental caries, and dental erosion and can decrease quality of life due to issues such as food intake problems and depression. The estimated prevalence of persistent xerostomia varies between 10% and 50%, with a conservative estimate of 20% in the general population. It is also more commonly found in women (up to 30%) and older adults (up to 50%) [2,4,5,6], and medications and diseases, as well as aging itself, are generally considered to be important factors [7,8]. However, there is no permanent solution approved by the US Food and Drug Administration for salivary gland hypofunction and resultant xerostomia [9,10,11]. This is also why more research on the mechanism by which xerostomia occurs is needed. Herein, we summarize the mechanisms of salivation at the cellular level and targeted studies of xerostomia.

2. Unidirectional Movement of Fluid in the Salivary Glands

2.1. Structure of the Salivary Glands

Saliva performs a variety of functions essential for oral and systemic health. These include moisturizing and lubricating the mouth; enabling gustatory and olfactory sensation; protecting the teeth and oropharyngeal mucosa; facilitating speech articulation; allowing mastication, swallowing, and digestion; and maintaining a balanced microbiome [12,13,14,15,16,17,18,19]. The salivary glands, which are exocrine glands, secrete saliva, which is a mixture of proteins and fluids, into the mouth. A healthy adult produces between 0.5 and 1.5 L of saliva per day, 90% of which is produced by the three main salivary glands: parotid (PAR), submandibular (SM), and sublingual (SL) glands [20,21].
Most of the secretion from the PAR glands occurs in response to stimuli, while the SM and SL glands are responsible for the majority of unstimulated saliva production [22]. These glands differ in the types of secretion they produce: the PAR glands produce a serous, watery secretion; the SM glands produce a mixed serous and mucous secretion; and the SL glands secrete saliva that is predominantly mucous in character [22]. One striking example of a gland-specific expression is salivary amylase, which shows abundant expression at the protein level in the PAR and SM glandular tissue while being virtually absent in the SL glands [23]. This functional specialization of the adult salivary glands occurs during late-stage development [23]. In 2020, a new set of salivary glands, called the tubarial glands, was suggested as a fourth pair of salivary glands; these glands are situated posteriorly in the nasopharynx [24]. In addition, hundreds of minor salivary glands are distributed throughout the oral cavity, among which glands in the lower lip are easily biopsied and used clinically to diagnose Sjögren’s syndrome. Some studies have obtained RNA-seq data that suggest that cellular heterogeneity within gland types underlies gland-specific protein secretions [23].
The secretion of saliva from the three main salivary glands into the oral cavity occurs through their respective ducts. Stensen’s duct pierces the buccinator and connects the PAR gland to the buccal mucosa adjacent to the maxillary second molar [25,26]. Wharton’s duct is the main excretory duct of the SM glands and arises from the smaller, deep lobe inferior to the mucosa of the floor of the mouth and opens into the oral cavity under the tongue by the lingual frenulum at the SL caruncle [25,26]. The SL gland drains through a series of short ducts, all of which open into the floor of the mouth and are collectively termed the ducts of Rivinus [25,26].

2.2. Polarized Acinar Cells and Support Cells

To understand the mechanism of salivation, it is important to understand the structure of the cell level constituting the salivary gland. The salivary glands are composed of various epithelial cells, including acinar cells, which produce saliva; ductal cells, which transport saliva to the oral cavity; and myoepithelial cells, which facilitate the secretion of saliva [22].
Acini are formed by clusters of several pyramidal secretory cells, acinar cells, and are identified by the expression of markers, such as the water channel aquaporin 5 (AQP5) and the transcription factor muscle, intestine, and stomach expression 1 (Mist1) [27,28,29,30]. These cells can be serous, mucous, or seromucous, depending on the nature of their secretions and are present in relative proportions varying between glands and species [31,32,33]. Acini are linked to the lateral membrane through tight junctions formed with adhesion molecules, and this structure serves to prevent lateral movement of membrane proteins between the apical and basolateral membranes, contributing to cell polarity [34,35,36]. In the salivary glands, tight junctions permit unidirectional salivary secretion and maintain a cellular barrier between blood and tissue fluid [36].
The ductal system of the salivary glands serves as a conduit to modify the electrolyte content of saliva and to transport secretions to the oral cavity. In general, acinar cells secrete an isotonic plasma-like fluid, which is deposited in the lumen [37,38,39]. As it passes through the ductal system, saliva is progressively transformed into a hypotonic solution by the selective reabsorption of certain ions [40,41]. The intercalated ducts (IDs), which are the parts of an exocrine gland leading directly from the acinus to striated ducts (SDs), are formed from a single layer of cuboidal cells with a central nucleus and small secretory granules containing lysozyme and lactoferrin [22,25,33]. The SDs, which are lined by a long columnar epithelium with a central nucleus, participate in bidirectional transport and reabsorption of electrolytes and are characterized by numerous mitochondria forming cytoplasmic folds or striations in the basolateral membrane [25,33]. Along with the IDs, these function to modify salivary fluid by secreting bicarbonate (HCO3−) and potassium (K+) and reabsorbing sodium (Na+) and chloride (Cl−), making the saliva hypotonic. They compose most of the duct systems in the major salivary glands [33,42] and drain into interlobular ducts situated between the lobules of the gland.
Myoepithelial cells surround acinar cells and are sometimes found around the IDs [43]. These cells are smooth muscle epithelial cells characterized by the expression of contractile proteins [44]. Thus, these are essential for the contractile process around acinar cells to promote salivary excretion in response to nerve stimulation [45,46,47].

3. Salivation by G-Protein-Coupled Receptor (GPCR)-Mediated Intracellular Calcium (Ca2+) Signaling

3.1. Mode of Action of Salivation

The salivary response to seeing or even imagining sour food occurs because the salivary glands in the oral system receive strong neural input. Salivation is primarily under the control of the autonomic nervous system and is regulated by neurotransmitters and hormones [41,48,49]. Fluid secretion is initiated primarily by the binding of neurotransmitters released from parasympathetic nerves to a specific GPCR. Here, an increase in the intracellular Ca2+ concentration ([Ca2+]i) stimulated by neurotransmitter–GPCR binding in acinar cells is a major trigger for salivation [50,51]. Protein secretion from the salivary glands is regulated primarily by intracellular 3′,5′-cyclic adenosine monophosphate (cyclic AMP) via sympathetic nerves [50]. Cyclic AMP signaling contributes to digestion by lubricating food when chewing and swallowing, and it exerts important antiviral and antibacterial effects on oral tissues (Figure 1).

3.2. GPCRs as Keys for Cell-to-Cell Communication

Salivary gland cells are non-excitatory cells that lack voltage-sensitive channels and communicate with other cells, such as neurons, through GPCRs. Thus, saliva secretion begins with the activation of specific GPCRs on released neurotransmitters [38,52,53], and GPCR-mediated signaling and salivary gland dysfunction are closely related [51,52,53,54]. mAChRs, specifically M3 subtype mAChRs (M3 mAChRs), are essential for the parasympathetic control of salivation in mice [53,55]. In the case of M1 or M3 single-knockout (KO) mice, the amount of pilocarpine-induced salivation was greatly reduced at a low concentration (1 mg/kg), but there was no significant difference compared with wild-type mice at a high concentration (15 mg/kg). In the case of double-KO mice, salivation was completely lost regardless of the pilocarpine concentration [55]. Carbachol (CCh)-induced increased [Ca2+]i in SM gland cells showed little difference in M1 KO mice compared with control mice but was greatly reduced in M3 KO mice and completely lost in double-KO mice [53]. Two-dimensional Ca2+ imaging analysis in response to CCh in individual acinar cell clusters suggested that the distribution of M1 in SM gland acini is not ubiquitous and that some acinar cells express M1 at a high level [53]. mAChRs are expressed at different levels of abundant subtypes by a gland or species type, and human labial glands express M1, M3, and M5 mAChRs [56]. Interestingly, upregulation of M3, M4, and M5 expression was observed in samples from patients with Sjögren’s syndrome [56,57].
In addition to mAChRs, a series of GPCRs, including GPR39, histamine H1 receptor, sphingosine–1–phosphate (S1P) receptor, bradykinin receptor, and P2Y2 receptor (P2Y2R), has been investigated to identify salivary gland-related functions [52,58,59,60,61]. GPR39 is a type of GPCR with zinc as a ligand and is expressed in human SM gland tissues [52]. Interestingly, this study showed that salivary secretion significantly increased when human subjects gargled with a zinc-containing solution. These effects were observed both in a normal group and various hyposalivation groups, including a group of patients with Sjögren’s syndrome [52]. In primary cultured cells of the human SM gland and human SM gland (HSG) cell lines, histamine increased the [Ca2+]i, and the histamine H1 receptor was expressed [59]. Other types of receptors, including S1P 1, 2, 3, and 4 receptors, are expressed in human SM gland cells [60]. S1P triggers Ca2+ signaling and induces the expression of interleukin 6 (IL-6) and Fas, which are known to be involved in a Sjögren’s syndrome-related apoptotic pathway [60]. Bradykinin B2 receptors are expressed in human SM gland tissue, and treatment with bradykinin induces intracellular Ca2+ signaling [61]. P2 purinergic receptors for extracellular nucleotides, including P2Y1 and P2Y2, are expressed in rat SM acinar and ductal cells and are involved in intracellular Ca2+ signaling [62,63,64,65]. In particular, due to its ability to stimulate water transport across epithelial cell membranes, the P2Y2R agonist diquafosol has undergone human clinical trials for the treatment of dry eye disease and is currently approved for human use in South Korea and Japan under the trade name Diquas [66,67,68].

3.3. Stimulation of Fluid Secretion by GPCR-Mediated Increases in [Ca2+]i in Acinar Cells

The salivary gland cells regulate their secretions through neurotransmitter-generated Ca2+ signaling. This is regulated by autonomic sympathetic and parasympathetic stimuli. In particular, ACh secreted from parasympathetic nerves is known to be the most important salivary secretory factor in the salivary glands. Enhancing fluid secretion in the salivary glands requires a series of processes, including activation of membrane receptors, including mAChRs, through binding between neurotransmitters and specific GPCRs, increases in cytoplasmic [Ca2+]i, and stimulation of ion transport pathways. When there is an increase in [Ca2+]i in the acinar cells, ion channel activity is regulated in various domains of the cells, the AQP5 channels are translocated to the apical membrane, and water secretion occurs.
Two steps (Ca2+ release from the ER and Ca2+ influx via the plasma membrane) are required to increase [Ca2+]i in the salivary glands and maintain the saliva secretion state (Figure 2). Stimulation of GPCRs, such as mAChRs and α1-adrenergic receptors, results in phospholipase C (PLC) activation. Sequentially, PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). The initial increase in [Ca2+]i after external stimulation of acinar cells is triggered by the release of Ca2+ from the ER via the binding of cytosolic IP3 and IP3 receptors (IP3Rs) at the ER membrane. In exocrine gland cells, IP3R2 and IP3R3 are concentrated in the apical pole of the cell [69,70], and in response to external stimuli, [Ca2+]i increases in the apical region, spreads to the basal pole, and activates various ion channels and transporters to coordinate fluid secretion [41,71,72,73]. Pilocarpine-induced salivation is seriously impaired in IP3R2 and IP3R3 double-KO mice, which lose weight and die within four weeks without wet mash food [74].
The IP3-induced increase in [Ca2+]i from the ER is essentially transient in the absence of extracellular Ca2+ [49]. Subsequent activation of store-operated Ca2+ entry (SOCE) converts the transient increase in [Ca2+]i into a sustained increase essential for long-term salivation [49] (Figure 2). Ca2+ depletion of the ER initiates the activation of SOCE [49,72]. Stromal interaction molecule–1 (STIM1) at the ER membrane acts as a Ca2+ sensor, which causes a conformational change when the concentration of Ca2+ in the ER is lowered and forms SOCE with Orai channels or transient receptor potential canonical (TRPC) channels expressed in the plasma membrane of acinar cells [75,76,77,78,79]. This process allows extracellular Ca2+ to enter the cell. Orai1 is the best characterized among the members of the Orai channel family, and it generates a highly Ca2+-sensitive, inwardly rectifying Ca2+ current when activated by STIM1 [77,79,80]. TRPC channels function as Ca2+-permeable nonselective cation channels, and all members are activated in response to PIP2 hydrolysis stimulated by neurotransmitters [81,82]. TRPC1 is an essential channel for salivary gland function, and lack of this channel results in an attenuation of store-operated Ca2+ current and a significant loss of fluid secretion [75,76]. Perturbation of SOCE activity is thought to be an important toxic mechanism because SOCE is required for the maintenance of a constant intracellular Ca2+ pool and GPCR signaling [83].
[Ca2+]i plays a particularly important role in regulating K+, Na+, and Cl− fluxes and salivary secretion in acinar cells. Salivation is initiated when an increased [Ca2+]i activates K+ and Cl− channels and is maintained as long as this is sustained [41,49]. For fluid secretion, transepithelial transport of Cl− from the basolateral to the apical side of the cell is required, and Na+ flux through the tight junction leads to the accumulation of NaCl in the lumen, resulting in water secretion through the AQP5 channel expressed in the apical membrane with the generated osmotic gradient [41,49]. In addition, the cell enters a hyperpolarized state through K+ efflux via the apical and basolateral membranes to support fluid secretion. [Ca2+]i is maintained at approximately 50–100 nM in resting cells, which is less than the threshold required to activate the K+ and Cl− channels [49].
Aquaporins (AQPs), a family of transmembrane channel proteins, are responsible for water transcellular permeability in most living organisms [84]. In mammals, AQPs are largely divided into classical AQPs permeable only to water (AQP1, AQP2, AQP4, AQP5, AQP6, and AQP8) and aquaglyceroporins permeable to small solutes such as glycerol and urea in addition to water (AQP3, AQP7, AQP9, and AQP10) [85,86,87]. In human salivary glands, AQP1 expression is restricted to the vascular endothelium and myoepithelial cells surrounding acini [29,88,89]. In acinar cells, AQP3, AQP4, and AQP5 are expressed, and the subcellular localization enriched in each is different [29,88,89,90,91]. Expression of AQP3, an aquaglyceroporin, has been detected at the apicolateral membrane of serous cells and at the apical pole of mucous acinar cells [29], while AQP4 expression has been localized to the basal membrane of acinar cells [90]. AQP5 is predominantly expressed at the apical membrane in acinar cells and not expressed in mature ducts [29,88,89,91]. AQP5 plays a key role in the secretion of saliva, and briefly, activation of subtype M1 and M3 mAChRs leads to an increased [Ca2+]i that induces AQP5 trafficking to the acinar apical membrane [92,93,94,95]. Parasympathectomy has been found to significantly decrease salivary AQP5 protein levels without affecting mRNA levels [96], through a post-transcriptional mechanism involving protein degradation [91,97]. The neural signal via the parasympathetic nerve innervating the SM glands, i.e., the chorda tympani nerve, has been suggested to be responsible for maintaining a certain degree of AQP5 expression [96]. Sympathetic activation leads to increased cAMP and a subsequent increase in RNA levels and the translocation of AQP5 to the cell apical membrane [91,98,99]. AQP5 KO mice presented an approximately 60% reduction in pilocarpine-induced saliva secretion, indicating that AQP5 plays a major role in water permeability in acinar cells and saliva secretion [94,95].

4. Increasing Prevalence of Xerostomia

The majority of the 550,000 patients who undergo radiation treatment for head and neck cancer annually and more than 4 million patients with Sjögren’s syndrome worldwide suffer from salivary gland dysfunction [100]. More than 400 different drugs, including antidepressants, antipsychotics, antihistamines, antihypertensives, and others, are also major causes [8,101,102,103,104,105]. Aging itself is also a cause of xerostomia, but its incidence continues to increase as polypharmacy among the elderly increases [106,107]. The combined number of multiple drugs greatly increases xerostomia, and among them, long-term use of drugs, including psychotropic drugs, causes chronic xerostomia and significantly reduces the quality of life. However, there is currently no permanent curative therapy, and the general management approach is directed at palliative treatment for the relief of symptoms and prevention of oral complications [104,108]. Systemic sialagogues approved by the Food and Drug Administration (FDA) for salivary gland dysfunction include muscarinic agonists, such as pilocarpine and cevimeline, as mimic form parasympathetic nerve action [109,110]. However, since mAChRs are widely expressed in various organs and tissues of the body, their use has various side effects [9,10,11].

4.1. Xerogenic Drugs as the Most Common Cause of Xerostomia

Drugs are the most frequent cause of dry mouth [111] and are called xerogenic drugs [112] (Table 1). These include antidepressants, antiemetics, antihistamines, antihypertensives, antipsychotics, appetite suppressants, anxiolytics, bronchodilators, cardiovascular agents, and muscle relaxants [8,101,102,103,104,105]. Some cause subjective dry mouth symptoms, and many can cause decreased salivation. Although there appear to be several mechanisms by which drugs can cause dry mouth, few have been subjected to in-depth scientific investigation [111]. Early antidepressants, including tricyclic antidepressants (TCAs), unfortunately block histaminergic, cholinergic, and α1-adrenergic receptor sites, resulting in a variety of adverse drug reactions (ADRs), including dry mouth as well as weight gain, constipation, drowsiness, and dizziness [111]. Muscarinic receptor antagonists, which are recommended as first-line therapy for an overactive bladder, can also cause dry mouth [111].
The likelihood of xerostomia increases with the total number of medications taken, regardless of whether the individual medications cause dry mouth. There are many other types of receptors for endogenous substances in the salivary glands that can be causes of drug-induced dry mouth, but anticholinergic actions contribute significantly. Synergistic effects of drug combinations contribute to xerostomia; in addition, although saliva flow does not necessarily decrease with age, older people are more likely than younger people to develop xerostomia due to the increased prevalence of chronic conditions requiring pharmacological treatment [106,113]. Drug-induced xerostomia is usually reversible, but the conditions for which these drugs are prescribed are often chronic [114]. Long-term treatment for schizophrenia with conventional phenothiazine antipsychotics is commonly associated with ADRs, including dry mouth [111]. Cardiovascular medications in hospitalized elderly patients and respiratory diseases in the elderly outpatients are the main factors for xerostomia, but the use of psychiatric drugs is also the strongest explanatory factor for all patients [7].

4.2. Systemic Diseases and Salivary Gland Disorders That Compromise Glandular Tissue Integrity

Systemic diseases that affect the salivary glands can cause salivary dysfunction, resulting in xerostomia [115] (Table 2). Among these, severe hyposalivation is frequently caused by Sjögren’s syndrome, a chronic autoimmune disease [116]. Excessive infiltration of inflammatory cells, resulting in increased production of cytokines and degradation of tissue proteins, destroys the acinar cells and interferes with salivary synthesis, resulting in dysfunction of the salivary glands [117]. Multiple innate immune pathways, including the nuclear factor-κB pathway, are likely dysregulated in the salivary gland epithelium in Sjögren’s syndrome [118]. Thus, both generic and oral health-related quality of life are poor in these patients [116]. Intraoral imaging using ultra-high frequency ultrasonography, a recently introduced diagnostic technique, plays an increasingly important role in small salivary gland biopsy and subsequent focal scoring, which are critical in the diagnostic workup of this disease [119,120].
Radiation therapy is an important treatment for patients with head and neck cancer. However, the salivary glands are often inadvertently irradiated and damaged because they are within the irradiated area [121]. Cumulative exposure to radiation causes excessive destruction of saliva-producing acini and reduced salivary flux [122,123]. Many advances in the management of radiation-induced salivary gland hypofunction still only offer partial protection [123]. Decreased salivation in these patients has serious consequences for oral somatosensory alterations that can lead to malnutrition [124].
Salivary gland tumors are uncommon, representing less than approximately 5% of all cancers of the head and neck [125]. Surgery is usually performed to remove the tumor and surrounding tissue, but this can also lead to reduced salivary gland function and xerostomia [126].
Both unstimulated and stimulated salivation decrease with age in humans [127]. Histological studies have demonstrated that with age, the mean volume of acini decreases by approximately 30% in the SM glands, nearly 25% in the SL glands, and approximately 12% in the PAR glands [107]. In addition, the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells in the SM glands has been found to increase with age, suggesting that cell turnover and cellular changes contribute to age-dependent salivary gland dysfunction [128].

4.3. Current Palliative Care and Pharmacological Therapies

Systemic sialagogues mimic the neural signals that stimulate saliva production in the epithelium. Anterior sialagogues mentioned by the FDA and the National Institute for Health and Care Excellence include pilocarpine and cevimeline [109,110], which stimulate salivary tissue. Pilocarpine is a nonselective muscarinic agonist with a relatively high affinity for CNS muscarinic receptors and cevimeline has a higher affinity for M1 and M3 mAChRs. Head and neck radiation-treated patients with established hyposalivation respond minimally to systemic sialagogues [129]. In addition, since mAChRs are widely expressed in the body, the use of these drugs is associated with various side effects such as nausea, diarrhea, increased urinary frequency, excessive sweating, cutaneous vasodilation, bronchoconstriction, hypotension, and bradycardia [9,10,11].
Saliva substitutes or artificial saliva are often prescribed to temporarily relieve xerostomia. They generally contain a thickening agent and have protective properties but poor antibacterial and antifungal properties [130]. Most saliva substitutes aim to mimic the rheological properties of saliva and consist of rheological modifiers such as xanthan and guar gums, as well as carboxymethyl cellulose or hydroxyethyl cellulose, glycerol, mucins, electrolytes, preservatives, and sweeteners. Saliva substitutes have not yet been able to mimic the antibacterial properties of saliva [130].
Mouth rinses, mouthwashes, and toothpaste can provide short-term relief from dry mouth and keep the patient’s mouth, teeth, and gums healthy. Such mouth rinses can greatly increase saliva volume and improve pH buffering [131]. However, similar to saliva substitutes, these treatments only treat symptoms for a short period of time (up to 4 h) and do not solve the underlying clinical problem.

5. Conclusions

Normal salivation is important for oral and overall health and wellbeing. Xerostomia is clearly a problem faced by an increasing proportion of the population. Accordingly, elucidating the mechanisms leading to the loss of salivary secretion and those involved in functional rescue should be a major focus of salivary research in the future. Acinar cells are polarized and are responsible for the unidirectional movement of fluid. Cellular heterogeneity among gland types derived from RNA-seq data suggests that various cells are coordinated within the salivary gland. Further elucidating this diversity will require a detailed study of the components of each cell unit. Importantly, saliva secretion is precisely regulated by GPCR-mediated intracellular Ca2+ signaling. Therefore, it is expected that regulators controlling the exocrine intracellular Ca2+ mechanism contribute directly to salivation. Key components involved in intracellular Ca2+ signaling include GPCR, IP3R, SOCE, and AQP5, all of which can be targets of medication or diseases. Conversely, acinar cell-specific GPCR agonists, such as mAChR and P2Y2R agonists, are potential therapeutic candidates that can regulate intracellular Ca2+ signaling at specific cellular units.

Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2021R1C1C2011217).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The author declares no conflict of interest.

References

  1. Scully, C. 8—Dry mouth (xerostomia and hyposalivation). In Oral and Maxillofacial Medicine, 3rd ed.; Scully, C., Ed.; Churchill Livingstone: London, UK, 2013; pp. 91–97. [Google Scholar]
  2. Furness, S.; Worthington, H.V.; Bryan, G.; Birchenough, S.; McMillan, R. Interventions for the management of dry mouth: Topical therapies. Cochrane Database Syst. Rev. 2011, 7, CD008934. [Google Scholar] [CrossRef] [PubMed]
  3. Ship, J.A.; Fox, P.C.; Baum, B.J. How much saliva is enough? ‘Normal’ function defined. J. Am. Dent. Assoc. 1991, 122, 63–69. [Google Scholar] [CrossRef] [PubMed]
  4. Orellana, M.; Lagravère, M.; Boychuk, D.; Major, P.; Flores-Mir, C.; Ortho, C. Prevalence of xerostomia in population-based samples: A systematic review. J. Public Health Dent. 2006, 66, 152–158. [Google Scholar] [CrossRef] [PubMed]
  5. Villa, A.; Abati, S. Risk factors and symptoms associated with xerostomia: A cross-sectional study. Aust. Dent. J. 2011, 56, 290–295. [Google Scholar] [CrossRef]
  6. Hopcraft, M.S.; Tan, C. Xerostomia: An update for clinicians. Aust. Dent. J. 2010, 55, 238–244; quiz 353. [Google Scholar] [CrossRef]
  7. Pajukoski, H.; Meurman, J.; Halonen, P.; Sulkava, R. Prevalence of subjective dry mouth and burning mouth in hospitalized elderly patients and outpatients in relation to saliva, medication, and systemic diseases. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endodontol. 2001, 92, 641–649. [Google Scholar] [CrossRef]
  8. Thomson, W.M.; Smith, M.B.; Ferguson, C.A.; Moses, G. The Challenge of Medication-Induced Dry Mouth in Residential Aged Care. Pharmacy 2021, 9, 162. [Google Scholar] [CrossRef]
  9. Chitapanarux, I.; Kamnerdsupaphon, P.; Tharavichitkul, E.; Sumitsawan, Y.; Sittitrai, P.; Pattarasakulchai, T.; Lorvidhaya, V.; Sukthomya, V.; Pukanhaphan, N.; Traisatit, P. Effect of oral pilocarpine on post-irradiation xerostomia in head and neck cancer patients: A single-center, single-blind clinical trial. J. Med. Assoc. Thail. 2008, 91, 1410–1415. [Google Scholar]
  10. Cifuentes, M.; Del Barrio-Díaz, P.; Vera-Kellet, C. Pilocarpine and artificial saliva for the treatment of xerostomia and xerophthalmia in Sjögren syndrome: A double-blind randomized controlled trial. Br. J. Dermatol. 2018, 179, 1056–1061. [Google Scholar] [CrossRef]
  11. Cheng, C.Q.; Xu, H.; Liu, L.; Wang, R.-N.; Liu, Y.-T.; Li, J.; Zhou, X.-K. Efficacy and safety of pilocarpine for radiation-induced xerostomia in patients with head and neck cancer: A systematic review and meta-analysis. J. Am. Dent. Assoc. 2016, 147, 236–243. [Google Scholar] [CrossRef]
  12. Pedersen, A.M.L.; Sørensen, C.E.; Proctor, G.B.; Carpenter, G.; Ekström, J. Salivary secretion in health and disease. J. Oral Rehabil. 2018, 45, 730–746. [Google Scholar] [CrossRef] [PubMed]
  13. Kilian, M.; Chapple, I.L.C.; Hannig, M.; Marsh, P.D.; Meuric, V.; Pedersen, A.M.L.; Tonetti, M.S.; Wade, W.G.; Zaura, E. The oral microbiome—An update for oral healthcare professionals. Br. Dent. J. 2016, 221, 657–666. [Google Scholar] [CrossRef]
  14. Marsh, P.D.; Do, T.; Beighton, D.; Devine, D.A. Influence of saliva on the oral microbiota. Periodontology 2000 2016, 70, 80–92. [Google Scholar] [CrossRef]
  15. Dawes, C.; Pedersen, A.M.L.; Villa, A.; Ekström, J.; Proctor, G.B.; Vissink, A.; Aframian, D.; McGowan, R.; Aliko, A.; Narayana, N.; et al. The functions of human saliva: A review sponsored by the World Workshop on Oral Medicine VI. Arch. Oral Biol. 2015, 60, 863–874. [Google Scholar] [CrossRef] [PubMed]
  16. Carpenter, G.H. The secretion, components, and properties of saliva. Annu. Rev. Food Sci. Technol. 2013, 4, 267–276. [Google Scholar] [CrossRef]
  17. Pedersen, A.M.L.; Bardow, A.; Jensen, S.B.; Nauntofte, B. Saliva and gastrointestinal functions of taste, mastication, swallowing and digestion. Oral Dis. 2002, 8, 117–129. [Google Scholar] [CrossRef] [PubMed]
  18. Humphrey, S.P.; Williamson, R.T. A review of saliva: Normal composition, flow, and function. J. Prosthet. Dent. 2001, 85, 162–169. [Google Scholar] [CrossRef]
  19. Mandel, I.D. The functions of saliva. J. Dent. Res. 1987, 66, 623–627. [Google Scholar] [CrossRef]
  20. Iorgulescu, G. Saliva between normal and pathological. Important factors in determining systemic and oral health. J. Med. Life 2009, 2, 303–307. [Google Scholar]
  21. Mese, H.; Matsuo, R. Salivary secretion, taste and hyposalivation. J. Oral Rehabil. 2007, 34, 711–723. [Google Scholar] [CrossRef]
  22. Chibly, A.M.; Aure, M.; Patel, V.; Hoffman, M. Salivary gland function, development, and regeneration. Physiol. Rev. 2022, 102, 1495–1552. [Google Scholar] [CrossRef]
  23. Saitou, M.; Gaylord, E.A.; Xu, E.; May, A.J.; Neznanova, L.; Nathan, S.; Grawe, A.; Chang, J.; Ryan, W.; Ruhl, S.; et al. Functional Specialization of Human Salivary Glands and Origins of Proteins Intrinsic to Human Saliva. Cell Rep. 2020, 33, 108402. [Google Scholar] [CrossRef] [PubMed]
  24. Valstar, M.H.; de Bakker, B.S.; Steenbakkers, R.J.; de Jong, K.H.; Smit, L.A.; Nulent, T.J.K.; van Es, R.J.; Hofland, I.; de Keizer, B.; Jasperse, B.; et al. The tubarial salivary glands: A potential new organ at risk for radiotherapy. Radiother. Oncol. 2021, 154, 292–298. [Google Scholar] [CrossRef]
  25. Ghannam, M.G.; Singh, P.V. Anatomy, Head and Neck, Salivary Glands. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2022. [Google Scholar]
  26. Holmberg, K.V.; Hoffman, M.P. Anatomy, biogenesis and regeneration of salivary glands. Monogr. Oral Sci. 2014, 24, 1–13. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Pin, C.L.; Bonvissuto, A.C.; Konieczny, S.F. Mist1 expression is a common link among serous exocrine cells exhibiting regulated exocytosis. Anat. Rec. 2000, 259, 157–167. [Google Scholar] [CrossRef]
  28. Larsen, H.S.; Aure, M.H.; Peters, S.; Larsen, M.; Messelt, E.B.; Galtung, H.K. Localization of AQP5 during development of the mouse submandibular salivary gland. J. Mol. Histol. 2011, 42, 71–81. [Google Scholar] [CrossRef] [Green Version]
  29. de Paula, F.; Teshima, T.H.N.; Hsieh, R.; Souza, M.M.; Coutinho-Camillo, C.M.; Nico, M.M.S.; Lourenco, S.V. The expression of water channel proteins during human salivary gland development: A topographic study of aquaporins 1, 3 and 5. J. Mol. Histol. 2017, 48, 329–336. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  30. Hsieh, M.S.; Jeng, Y.M.; Lee, Y.H. Mist1: A novel nuclear marker for acinic cell carcinoma of the salivary gland. Virchows Arch. 2019, 475, 617–624. [Google Scholar] [CrossRef]
  31. Garrett, J.R.; Ekström, J.; Anderson, L.C. Glandular Mechanisms of Salivary Secretion; Karger Medical and Scientific Publishers: Basel, Switzerland, 1998; Volume 10. [Google Scholar]
  32. Berkovitz, B.K.; Holland, G.R.; Moxham, B.J. A Color Atlas and Text of Oral Anatomy, Histology and Embryology; Mosby Elsevier Health Science: St. Louis, MO, USA, 1992. [Google Scholar]
  33. de Paula, F.; Teshima, T.H.N.; Hsieh, R.; Souza, M.M.; Nico, M.M.S.; Lourenco, S.V. Overview of Human Salivary Glands: Highlights of Morphology and Developing Processes. Anat. Rec. 2017, 300, 1180–1188. [Google Scholar] [CrossRef] [Green Version]
  34. Furuse, M.; Tsukita, S. Claudins in occluding junctions of humans and flies. Trends Cell Biol. 2006, 16, 181–188. [Google Scholar] [CrossRef]
  35. Miyoshi, J.; Takai, Y. Molecular perspective on tight-junction assembly and epithelial polarity. Adv. Drug Deliv. Rev. 2005, 57, 815–855. [Google Scholar] [CrossRef] [PubMed]
  36. Baker, O.J. Tight junctions in salivary epithelium. J. Biomed. Biotechnol. 2010, 2010, 278948. [Google Scholar] [CrossRef] [Green Version]
  37. Kondo, Y.; Nakamoto, T.; Jaramillo, Y.; Choi, S.; Catalan, M.; Melvin, J. Functional differences in the acinar cells of the murine major salivary glands. J. Dent. Res. 2015, 94, 715–721. [Google Scholar] [CrossRef] [Green Version]
  38. Lee, M.G.; Ohana, E.; Park, H.W.; Yang, D.; Muallem, S. Molecular mechanism of pancreatic and salivary gland fluid and HCO3 secretion. Physiol. Rev. 2012, 92, 39–74. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Catalán, M.A.; Nakamoto, T.; Gonzalez-Begne, M.; Camden, J.M.; Wall, S.M.; Clarke, L.L.; Melvin, J.E. Cftr and ENaC ion channels mediate NaCl absorption in the mouse submandibular gland. J. Physiol. 2010, 588, 713–724. [Google Scholar] [CrossRef] [PubMed]
  40. Proctor, G.B. The physiology of salivary secretion. Periodontology 2016, 70, 11–25. [Google Scholar] [CrossRef] [Green Version]
  41. Melvin, J.E.; Yule, D.; Shuttleworth, T.; Begenisich, T. Regulation of fluid and electrolyte secretion in salivary gland acinar cells. Annu. Rev. Physiol. 2005, 67, 445–469. [Google Scholar] [CrossRef]
  42. Tandler, B.; Gresik, E.W.; Nagato, T.; Phillips, C.J. Secretion by striated ducts of mammalian major salivary glands: Review from an ultrastructural, functional, and evolutionary perspective. Anat. Rec. 2001, 264, 121–145. [Google Scholar] [CrossRef]
  43. Redman, R.S. Myoepithelium of salivary glands. Microsc. Res. Technol. 1994, 27, 25–45. [Google Scholar] [CrossRef]
  44. Makarenkova, H.P.; Dartt, D.A. Myoepithelial Cells: Their Origin and Function in Lacrimal Gland Morphogenesis, Homeostasis, and Repair. Curr. Mol. Biol. Rep. 2015, 1, 115–123. [Google Scholar] [CrossRef] [Green Version]
  45. Hawley, D.; Tang, X.; Zyrianova, T.; Shah, M.; Janga, S.; Letourneau, A.; Schicht, M.; Paulsen, F.; Hamm-Alvarez, S.; Makarenkova, H.P.; et al. Myoepithelial cell-driven acini contraction in response to oxytocin receptor stimulation is impaired in lacrimal glands of Sjögren’s syndrome animal models. Sci. Rep. 2018, 8, 9919. [Google Scholar] [CrossRef] [Green Version]
  46. Emmelin, N.; Gjörstrup, P. On the function of myoepithelial cells in salivary glands. J. Physiol. 1973, 230, 185–198. [Google Scholar] [CrossRef] [PubMed]
  47. Lung, M.A. Autonomic nervous control of myoepithelial cells and secretion in submandibular gland of anaesthetized dogs. J. Physiol. 2003, 546, 837–850. [Google Scholar] [CrossRef]
  48. Ambudkar, I.S. Calcium signalling in salivary gland physiology and dysfunction. J. Physiol. 2016, 594, 2813–2824. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  49. Ambudkar, I.S. Ca2+ signaling and regulation of fluid secretion in salivary gland acinar cells. Cell Calcium 2014, 55, 297–305. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  50. Proctor, G.B.; Carpenter, G.H. Regulation of salivary gland function by autonomic nerves. Auton. Neurosci. 2007, 133, 3–18. [Google Scholar] [CrossRef]
  51. Ambudkar, I.S. Dissection of calcium signaling events in exocrine secretion. Neurochem. Res. 2011, 36, 1212–1221. [Google Scholar] [CrossRef] [Green Version]
  52. Kim, Y.-J.; Jo, Y.; Lee, Y.-H.; Park, K.; Park, H.-K.; Choi, S.-Y. Zn2+ stimulates salivary secretions via metabotropic zinc receptor ZnR/GPR39 in human salivary gland cells. Sci. Rep. 2019, 9, 17648. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Nakamura, T.; Matsui, M.; Uchida, K.; Futatsugi, A.; Kusakawa, S.; Matsumoto, N.; Nakamura, K.; Manabe, T.; Taketo, M.M.; Mikoshiba, K. M3muscarinic acetylcholine receptor plays a critical role in parasympathetic control of salivation in mice. J. Physiol. 2004, 558, 561–575. [Google Scholar] [CrossRef]
  54. Jin, M.; Hwang, S.-M.; Koo, N.-Y.; Kim, B.; Kho, H.-S.; Choi, S.-Y.; Song, Y.; Park, K. Autoantibodies in Sjögren’s syndrome patients acutely inhibit muscarinic receptor function. Oral Dis. 2012, 18, 132–139. [Google Scholar] [CrossRef]
  55. Gautam, D.; Heard, T.S.; Cui, Y.; Miller, G.; Bloodworth, L.; Wess, J. Cholinergic stimulation of salivary secretion studied with M1 and M3 muscarinic receptor single- and double-knockout mice. Mol. Pharmacol. 2004, 66, 260–267. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Ryberg, A.T.; Warfvinge, G.; Axelsson, L.; Soukup, O.; Götrick, B.; Tobin, G. Expression of muscarinic receptor subtypes in salivary glands of rats, sheep and man. Arch. Oral Biol. 2008, 53, 66–74. [Google Scholar] [CrossRef] [PubMed]
  57. Beroukas, D.; Goodfellow, R.; Hiscock, J.; Jonsson, R.; Gordon, T.; Waterman, S.A. Up-regulation of M3-muscarinic receptors in labial salivary gland acini in primary Sjögren’s syndrome. Lab Investig. 2002, 82, 203–210. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Khalafalla, M.G.; Woods, L.T.; Jasmer, K.; Forti, K.M.; Camden, J.M.; Jensen, J.L.; Limesand, K.H.; Galtung, H.K.; Weisman, G.A. P2 Receptors as Therapeutic Targets in the Salivary Gland: From Physiology to Dysfunction. Front. Pharmacol. 2020, 11, 222. [Google Scholar] [CrossRef] [Green Version]
  59. Kim, J.H.; Park, S.-H.; Moon, Y.W.; Hwang, S.; Kim, D.; Jo, S.-H.; Oh, S.B.; Kim, J.S.; Jahng, J.W.; Lee, J.-H.; et al. Histamine H1 receptor induces cytosolic calcium increase and aquaporin translocation in human salivary gland cells. J. Pharmacol. Exp. Ther. 2009, 330, 403–412. [Google Scholar] [CrossRef]
  60. Seo, J.; Koo, N.Y.; Choi, W.Y.; Kang, J.A.; Min, J.H.; Jo, S.H.; Lee, S.J.; Oh, S.B.; Kim, J.S.; Lee, J.H.; et al. Sphingosine-1-phosphate signaling in human submandibular cells. J. Dent. Res. 2010, 89, 1148–1153. [Google Scholar] [CrossRef]
  61. Lee, K.; Kim, Y.-J.; Choi, L.-M.; Choi, S.; Nam, H.; Ko, H.-Y.; Chung, G.; Lee, J.-H.; Jo, S.-H.; Lee, G.; et al. Human salivary gland cells express bradykinin receptors that modulate the expression of proinflammatory cytokines. Eur. J. Oral Sci. 2017, 125, 18–27. [Google Scholar] [CrossRef]
  62. Turner, J.; Landon, L.A.; Gibbons, S.J.; Talamo, B.R. Salivary gland P2 nucleotide receptors. Crit. Rev. Oral Biol. Med. 1999, 10, 210–224. [Google Scholar] [CrossRef]
  63. Lee, M.G.; Zeng, W.; Muallem, S. Characterization and localization of P2 receptors in rat submandibular gland acinar and duct cells. J. Biol. Chem. 1997, 272, 32951–32955. [Google Scholar] [CrossRef] [Green Version]
  64. Park, M.K.; Garrad, R.C.; Weisman, G.A.; Turner, J.T. Changes in P2Y1 nucleotide receptor activity during the development of rat salivary glands. Am. J. Physiol. Physiol. 1997, 272, C1388–C1393. [Google Scholar] [CrossRef]
  65. Baker, O.J.; Camden, J.M.; Rome, D.E.; Seye, C.I.; Weisman, G.A. P2Y2 nucleotide receptor activation up-regulates vascular cell adhesion molecule-1 [corrected] expression and enhances lymphocyte adherence to a human submandibular gland cell line. Mol. Immunol. 2008, 45, 65–75. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Tauber, J.; Davitt, W.F.; Bokosky, J.E.; Nichols, K.K.; Yerxa, B.R.; Schaberg, A.E.; LaVange, L.M.; Mills-Wilson, M.C.; Kellerman, D.J. Double-masked, placebo-controlled safety and efficacy trial of diquafosol tetrasodium (INS365) ophthalmic solution for the treatment of dry eye. Cornea 2004, 23, 784–792. [Google Scholar] [CrossRef]
  67. Koh, S. Clinical utility of 3% diquafosol ophthalmic solution in the treatment of dry eyes. Clin. Ophthalmol. 2015, 9, 865–872. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Takamura, E.; Tsubota, K.; Watanabe, H.; Ohashi, Y.; For the Diquafosol Ophthalmic Solution Phase 3 Study Group. A randomised, double-masked comparison study of diquafosol versus sodium hyaluronate ophthalmic solutions in dry eye patients. Br. J. Ophthalmol. 2012, 96, 1310–1315. [Google Scholar] [CrossRef] [PubMed]
  69. Kiselyov, K.; Wang, X.; Shin, D.M.; Zang, W.; Muallem, S. Calcium signaling complexes in microdomains of polarized secretory cells. Cell Calcium 2006, 40, 451–459. [Google Scholar] [CrossRef] [PubMed]
  70. Li, Q.; Luo, X.; Muallem, S. Functional Mapping of Ca2+ Signaling Complexes in Plasma Membrane Microdomains of Polarized Cells. J. Biol. Chem. 2004, 279, 27837–27840. [Google Scholar] [CrossRef] [Green Version]
  71. Mikoshiba, K.; Hisatsune, C.; Futatsugi, A.; Mizutani, A.; Nakamura, T.; Miyachi, K. The role of Ca2+ signaling in cell function with special reference to exocrine secretion. Cornea 2008, 27, S3–S8. [Google Scholar] [CrossRef]
  72. Yule, D.I. Subtype-specific regulation of inositol 1,4,5-trisphosphate receptors: Controlling calcium signals in time and space. J. Gen. Physiol. 2001, 117, 431–434. [Google Scholar] [CrossRef] [Green Version]
  73. Ambudkar, I.S. Polarization of calcium signaling and fluid secretion in salivary gland cells. Curr. Med. Chem. 2012, 19, 5774–5781. [Google Scholar] [CrossRef]
  74. Futatsugi, A.; Nakamura, T.; Yamada, M.K.; Ebisui, E.; Nakamura, K.; Uchida, K.; Kitaguchi, T.; Takahashi-Iwanaga, H.; Noda, T.; Aruga, J.; et al. IP 3 Receptor types 2 and 3 mediate exocrine secretion underlying energy metabolism. Science 2005, 309, 2232–2234. [Google Scholar] [CrossRef]
  75. Liu, X.; Cheng, K.T.; Bandyopadhyay, B.; Pani, B.; Dietrich, A.; Paria, B.; Swaim, W.; Beech, D.; Yildrim, E.; Singh, B.; et al. Attenuation of store-operated Ca2+ current impairs salivary gland fluid secretion in TRPC1(-/-) mice. Proc. Natl. Acad. Sci. USA 2007, 104, 17542–17547. [Google Scholar]
  76. Hong, J.H.; Li, Q.; Kim, M.S.; Shin, D.M.; Feske, S.; Birnbaumer, L.; Cheng, K.T.; Ambudkar, I.S.; Muallem, S. Polarized but differential localization and recruitment of STIM1, Orai1 and TRPC channels in secretory cells. Traffic 2011, 12, 232–245. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Hogan, P.G.; Lewis, R.S.; Rao, A. Molecular basis of calcium signaling in lymphocytes: STIM and ORAI. Annu. Rev. Immunol. 2010, 28, 491–533. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  78. Cheng, K.T.; Ong, H.L.; Liu, X.; Ambudkar, I.S. Contribution and regulation of TRPC channels in store-operated Ca2+ entry. In Current Topics in Membranes; Academic Press Inc.: Cambridge, MA, USA, 2013; Volume 71, pp. 149–179. [Google Scholar]
  79. Yuan, J.P.; Zeng, W.; Dorwart, M.R.; Choi, Y.-J.; Worley, P.F.; Muallem, S. SOAR and the polybasic STIM1 domains gate and regulate Orai channels. Nat. Cell Biol. 2009, 11, 337–343. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Prakriya, M. The molecular physiology of CRAC channels. Immunol. Rev. 2009, 231, 88–98. [Google Scholar] [CrossRef] [Green Version]
  81. Birnbaumer, L.; Zhu, X.; Jiang, M.; Boulay, G.; Peyton, M.; Vannier, B.; Brown, D.; Platano, D.; Sadeghi, H.; Stefani, E.; et al. On the molecular basis and regulation of cellular capacitative calcium entry: Roles for Trp proteins. Proc. Natl. Acad. Sci. USA 1996, 93, 15195–15202. [Google Scholar] [CrossRef] [Green Version]
  82. Montell, C. The TRP superfamily of cation channels. Sci. STKE 2005, 2005, re3. [Google Scholar] [CrossRef] [Green Version]
  83. Lee, K.; Kim, Y.-J.; Cho, Y.Y.; Chung, S.; Jo, S.-H.; Choi, S.-Y. Polychlorinated biphenyl 19 blocks the most common form of store-operated Ca2+ entry through Orai. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2017, 390, 1221–1228. [Google Scholar] [CrossRef] [PubMed]
  84. D’Agostino, C.; Elkashty, O.; Chivasso, C.; Perret, J.; Tran, S.; Delporte, C. Insight into Salivary Gland Aquaporins. Cells 2020, 9, 1547. [Google Scholar] [CrossRef] [PubMed]
  85. Agre, P. Aquaporin water channels (Nobel Lecture). Angew. Chem. Int. Ed. 2004, 43, 4278–4290. [Google Scholar] [CrossRef]
  86. Ishibashi, K.; Morishita, Y.; Tanaka, Y. The Evolutionary Aspects of Aquaporin Family. Adv. Exp. Med. Biol. 2017, 969, 35–50. [Google Scholar] [CrossRef]
  87. Rojek, A.; Praetorius, J.; Frøkiaer, J.; Nielsen, S.; Fenton, R.A. A current view of the mammalian aquaglyceroporins. Annu. Rev. Physiol. 2008, 70, 301–327. [Google Scholar] [CrossRef]
  88. Stamboni, M.B.; Gomes, N.D.M.; de Souza, M.M.; Oliveira, K.K.; Arruda, C.F.J.; de Paula, F.; Bettim, B.B.; Marques, M.M.; Kowalski, L.P.; Pinto, C.A.L.; et al. Aquaporin 1, 3, and 5 Patterns in Salivary Gland Mucoepidermoid Carcinoma: Expression in Surgical Specimens and an In Vitro Pilot Study. Int. J. Mol. Sci. 2020, 21, 1287. [Google Scholar] [CrossRef] [Green Version]
  89. Delporte, C. Aquaporins in salivary glands and pancreas. Biochim. Biophys. Acta (BBA)—Gen. Subj. 2014, 1840, 1524–1532. [Google Scholar] [CrossRef] [PubMed]
  90. Sisto, M.; Lorusso, L.; Ingravallo, G.; Nico, B.; Ribatti, D.; Ruggieri, S.; Lofrumento, D.D.; Lisi, S. Abnormal distribution of AQP4 in minor salivary glands of primary Sjögren’s syndrome patients. Autoimmunity 2017, 50, 202–210. [Google Scholar] [CrossRef] [PubMed]
  91. Hosoi, K.; Yao, C.; Hasegawa, T.; Yoshimura, H.; Akamatsu, T. Dynamics of Salivary Gland AQP5 under Normal and Pathologic Conditions. Int. J. Mol. Sci. 2020, 21, 1182. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  92. Ishikawa, Y.; Eguchi, T.; Skowronski, M.T.; Ishida, H. Acetylcholine acts on M3 muscarinic receptors and induces the translocation of aquaporin5 water channel via cytosolic Ca2+ elevation in rat parotid glands. Biochem. Biophys. Res. Commun. 1998, 245, 835–840. [Google Scholar] [CrossRef] [PubMed]
  93. Tada, J.; Sawa, T.; Yamanaka, N.; Shono, M.; Akamatsu, T.; Tsumura, K.; Parvin, M.N.; Kanamori, N.; Hosoi, K. Involvement of Vesicle–Cytoskeleton Interaction in AQP5 Trafficking in AQP5-Gene-Transfected HSG Cells. Biochem. Biophys. Res. Commun. 1999, 266, 443–447. [Google Scholar] [CrossRef] [PubMed]
  94. Krane, C.M.; Melvin, J.E.; Nguyen, H.-V.; Richardson, L.; Towne, J.E.; Doetschman, T.; Menon, A.G. Salivary acinar cells from aquaporin 5-deficient mice have decreased membrane water permeability and altered cell volume regulation. J. Biol. Chem. 2001, 276, 23413–23420. [Google Scholar] [CrossRef] [Green Version]
  95. Ma, T.; Song, Y.; Gillespie, A.; Carlson, E.J.; Epstein, C.J.; Verkman, A.S. Defective secretion of saliva in transgenic mice lacking aquaporin-5 water channels. J. Biol. Chem. 1999, 274, 20071–20074. [Google Scholar] [CrossRef] [Green Version]
  96. Li, X.; Azlina, A.; Karabasil, M.R.; Purwanti, N.; Hasegawa, T.; Yao, C.; Akamatsu, T.; Hosoi, K. Degradation of submandibular gland AQP5 by parasympathetic denervation of chorda tympani and its recovery by cevimeline, an M3 muscarinic receptor agonist. Am. J. Physiol. Gastrointest. Liver Physiol. 2008, 295, G112–G123. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Azlina, A.; Javkhlan, P.; Hiroshima, Y.; Hasegawa, T.; Yao, C.; Akamatsu, T.; Hosoi, K. Roles of lysosomal proteolytic systems in AQP5 degradation in the submandibular gland of rats following chorda tympani parasympathetic denervation. Am. J. Physiol. Gastrointest. Liver Physiol. 2010, 299, G1106–G1117. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  98. Yang, F.; Kawedia, J.D.; Menon, A.G. Cyclic AMP regulates aquaporin 5 expression at both transcriptional and post-transcriptional levels through a protein kinase A pathway. J. Biol. Chem. 2003, 278, 32173–32180. [Google Scholar] [CrossRef] [Green Version]
  99. Chen, G.; Yao, C.; Hasegawa, T.; Akamatsu, T.; Yoshimura, H.; Hosoi, K. Effects of isoproterenol on aquaporin 5 levels in the parotid gland of mice in vivo. Am. J. Physiol. Metab. 2014, 306, E100–E108. [Google Scholar] [CrossRef] [Green Version]
  100. Rocchi, C.; Emmerson, E. Mouth-Watering Results: Clinical Need, Current Approaches, and Future Directions for Salivary Gland Regeneration. Trends Mol. Med. 2020, 26, 649–669. [Google Scholar] [CrossRef] [PubMed]
  101. Guggenheimer, J.; Moore, P.A. Xerostomia: Etiology, recognition and treatment. J. Am. Dent. Assoc. 2003, 134, 61–69. [Google Scholar] [CrossRef] [PubMed]
  102. Talha, B.; Swarnkar, S.A. Xerostomia. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2022. [Google Scholar]
  103. Tanasiewicz, M.; Hildebrandt, T.; Obersztyn, I. Xerostomia of Various Etiologies: A Review of the Literature. Adv. Clin. Exp. Med. 2016, 25, 199–206. [Google Scholar] [CrossRef] [Green Version]
  104. Turner, M.D. Hyposalivation and Xerostomia: Etiology, Complications, and Medical Management. Dent. Clin. N. Am. 2016, 60, 435–443. [Google Scholar] [CrossRef] [PubMed]
  105. Porter, S.R.; Scully, C.; Hegarty, A. An update of the etiology and management of xerostomia. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endodontol. 2004, 97, 28–46. [Google Scholar] [CrossRef]
  106. Gupta, A.; Epstein, J.B.; Sroussi, H. Hyposalivation in elderly patients. J. Can. Dent. Assoc. 2006, 72, 841–846. [Google Scholar]
  107. Toan, N.; Ahn, S.-G. Aging-Related Metabolic Dysfunction in the Salivary Gland: A Review of the Literature. Int. J. Mol. Sci. 2021, 22, 5835. [Google Scholar] [CrossRef]
  108. Chibly, A.M.; Nguyen, T.; Limesand, K.H. Palliative Care for Salivary Gland Dysfunction Highlights the Need for Regenerative Therapies: A Review on Radiation and Salivary Gland Stem Cells. J. Palliat. Care Med. 2014, 4, 1000180. [Google Scholar] [PubMed]
  109. Chambers, M.S.; Jones, C.U.; Biel, M.A.; Weber, R.S.; Hodge, K.M.; Chen, Y.; Holland, J.M.; Ship, J.A.; Vitti, R.; Armstrong, I.; et al. Open-label, long-term safety study of cevimeline in the treatment of postirradiation xerostomia. Int. J. Radiat. Oncol. 2007, 69, 1369–1376. [Google Scholar] [CrossRef] [PubMed]
  110. Takakura, A.; Moreira, T.S.; Laitano, S.; De Luca, L.; Renzi, A.; Menani, J.V. Central muscarinic receptors signal pilocarpine-induced salivation. J. Dent. Res. 2003, 82, 993–997. [Google Scholar] [CrossRef] [PubMed]
  111. Scully, C. Drug effects on salivary glands: Dry mouth. Oral Dis. 2003, 9, 165–176. [Google Scholar] [CrossRef]
  112. Loesche, W.J.; Bromberg, J.; Terpenning, M.S.; Bretz, W.A.; Dominguez, B.L.; Grossman, N.S.; Langmore, S.E. Xerostomia, xerogenic medications and food avoidances in selected geriatric groups. J. Am. Geriatr. Soc. 1995, 43, 401–407. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Tan, E.C.K.; Lexomboon, D.; Sandborgh-Englund, G.; Haasum, Y. Medications That Cause Dry Mouth as an Adverse Effect in Older People: A Systematic Review and Metaanalysis. J. Am. Geriatr. Soc. 2018, 66, 76–84. [Google Scholar] [CrossRef]
  114. Kapourani, A.; Kontogiannopoulos, K.N.; Manioudaki, A.-E.; Poulopoulos, A.K.; Tsalikis, L.; Assimopoulou, A.N.; Barmpalexis, P. A Review on Xerostomia and Its Various Management Strategies: The Role of Advanced Polymeric Materials in the Treatment Approaches. Polymers 2022, 14, 850. [Google Scholar] [CrossRef]
  115. Mortazavi, H.; Baharvand, M.; Movahhedian, A.; Mohammadi, M.; Khodadoustan, A. Xerostomia due to systemic disease: A review of 20 conditions and mechanisms. Ann. Med. Health Sci. Res. 2014, 4, 503–510. [Google Scholar] [CrossRef]
  116. Stewart, C.M.; Berg, K.M.; Cha, S.; Reeves, W.H. Salivary dysfunction and quality of life in Sjögren syndrome: A critical oral-systemic connection. J. Am. Dent. Assoc. 2008, 139, 291–299; quiz 358–359. [Google Scholar] [CrossRef]
  117. Pérez, P.; Kwon, Y.-J.; Alliende, C.; Leyton, L.; Aguilera, S.; Molina, C.; Labra, C.; Julio, M.; Leyton, C.; González, M.-J. Increased acinar damage of salivary glands of patients with Sjögren’s syndrome is paralleled by simultaneous imbalance of matrix metalloproteinase 3/tissue inhibitor of metalloproteinases 1 and matrix metalloproteinase 9/tissue inhibitor of metalloproteinases 1 ratios. Arthritis Rheum. 2005, 52, 2751–2760. [Google Scholar]
  118. Verstappen, G.M.; Pringle, S.; Bootsma, H.; Kroese, F.G.M. Epithelial–immune cell interplay in primary Sjögren syndrome salivary gland pathogenesis. Nat. Rev. Rheumatol. 2021, 17, 333–348. [Google Scholar] [CrossRef]
  119. Ferro, F.; Izzetti, R.; Vitali, S.; Aringhieri, G.; Fonzetti, S.; Donati, V.; Dini, V.; Mosca, M.; Gabriele, M.; Caramella, D.; et al. Ultra-high frequency ultrasonography of labial glands is a highly sensitive tool for the diagnosis of Sjögren’s syndrome: A preliminary study. Clin. Exp. Rheumatol. 2020, 38 (Suppl. S126), 210–215. [Google Scholar] [PubMed]
  120. Izzetti, R.; Ferro, F.; Vitali, S.; Nisi, M.; Fonzetti, S.; Oranges, T.; Donati, V.; Caramella, D.; Baldini, C.; Gabriele, M. Ultra-high frequency ultrasonography (UHFUS)-guided minor salivary gland biopsy: A promising procedure to optimize labial salivary gland biopsy in Sjögren’s syndrome. J. Oral Pathol. Med. 2021, 50, 485–491. [Google Scholar] [CrossRef] [PubMed]
  121. Ortholan, C.; Benezery, K.; Bensadoun, R.J. Normal tissue tolerance to external beam radiation therapy: Salivary glands. Cancer Radiother. 2010, 14, 290–294. [Google Scholar] [CrossRef] [PubMed]
  122. Vissink, A.; Jansma, J.; Spijkervet, F.K.L.; Burlage, F.R.; Coppes, R.P. Oral sequelae of head and neck radiotherapy. Crit. Rev. Oral Biol. Med. 2003, 14, 199–212. [Google Scholar] [CrossRef]
  123. Jensen, S.B.; Vissink, A.; Limesand, K.H.; Reyland, M.E. Salivary Gland Hypofunction and Xerostomia in Head and Neck Radiation Patients. J. Natl. Cancer Inst. Monogr. 2019, 2019, lgz016. [Google Scholar] [CrossRef] [PubMed]
  124. Riantiningtyas, R.R.; Carrouel, F.; Bruyas, A.; Bredie, W.L.; Kwiecien, C.; Giboreau, A.; Dougkas, A. Oral Somatosensory Alterations in Head and Neck Cancer Patients—An Overview of the Evidence and Causes. Cancers 2023, 15, 718. [Google Scholar] [CrossRef]
  125. Sun, E.C.; Curtis, R.; Melbye, M.; Goedert, J.J. Salivary gland cancer in the United States. Cancer Epidemiol. Biomark. Prev. 1999, 8, 1095–1100. [Google Scholar]
  126. Chuong, M.; Bryant, J.; Hartsell, W.; Larson, G.; Badiyan, S.; Laramore, G.E.; Katz, S.; Tsai, H.; Vargas, C. Minimal acute toxicity from proton beam therapy for major salivary gland cancer. Acta Oncol. 2020, 59, 196–200. [Google Scholar] [CrossRef]
  127. Yeh, C.K.; Johnson, D.A.; Dodds, M.W.J. Impact of aging on human salivary gland function: A community-based study. Aging Clin. Exp. Res. 1998, 10, 421–428. [Google Scholar] [CrossRef]
  128. Choi, J.-S.; Park, I.S.; Kim, S.-K.; Lim, J.-Y.; Kim, Y.-M. Analysis of age-related changes in the functional morphologies of salivary glands in mice. Arch. Oral Biol. 2013, 58, 1635–1642. [Google Scholar] [CrossRef] [PubMed]
  129. Gorsky, M.; Epstein, J.B.; Parry, J.; Epstein, M.S.; Le, N.D.; Silverman, S. The efficacy of pilocarpine and bethanechol upon saliva production in cancer patients with hyposalivation following radiation therapy. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endodontology 2004, 97, 190–195. [Google Scholar] [CrossRef] [PubMed]
  130. Güneri, P.; Alpöz, E.; Epstein, J.B.; Çankaya, H.; Ates, M. In vitro antimicrobial effects of commercially available mouth-wetting agents. Spec. Care Dent. 2011, 31, 123–128. [Google Scholar] [CrossRef]
  131. Takesh, T.; Ho, J.; Firmalino, M.V.; Islip, D.; Anbarani, A.; Wilder-Smith, P. Effects of a Novel Formulation on Oral Biofilm, pH Buffering, and Gingival Health in Patients with Dry Mouth. Int. J. Dent. 2018, 2018, 2748274. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Ijms 24 05358 g001 550
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 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.
Ijms 24 05358 g001
Ijms 24 05358 g002 550
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.
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.
Ijms 24 05358 g002
Table
Table 1. Xerogenic drugs.
Table 1. Xerogenic drugs.
ClassificationDrugs
AnalgesicsOpioids, pregabalin, tramadol.
AnticonvulsantsCarbamazepine, gabapentin, lamotrigine.
AntidepressantsTricyclics (e.g., amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine), selective serotonin reuptake inhibitors (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), serotonin and noradrenaline reuptake inhibitors (e.g., venlafaxine), and atypical antidepressants (e.g., bupropion, duloxetine, mirtazapine, trazodone).
AntiemeticsBuclizine, cyclizine, dimenhydrinate, meclizine, metocloopramide, prochloperazine, scopolamine, thiethylperazine, trimethobenzamide.
AntihistaminesFirst-generation antihistamines (carbinoxamine, clemastine dexchlorpheniramine, dimenhydranate, diphenhydramine, hydroxyzine, meclizine, promethazine), and second-generation antihistamines (cetirizine, desloratadine, fexofenadine, levocetirizine loratadine).
Antihypertensivesα-agonists (clonidine, guanabenz, guanfacine, methldopa), β-blockers (acebutolol, atenolol, bebivolol, betaxolol, bisoprolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, penbutolol, pindolol, propranolol, stalol, timolol), diuretics (bumetanide, furosemide, torsemide), Ca2+ channel blockers (amlodipine, diltiazem, felodipine, isradipine, nifedipine, nimodipine, verapamil), and angiotensin-converting enzyme inhibitors (benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril).
Antiparkinsonianamantadine, benztropine, bromocriptine, carbidopa, entcapone, levodopa, pramipexole, rasagiline, ropinirole, selegiline, trihexyphenidyl.
AntipsychoticsTypical antipsychotics (e.g., chlorpromazine, fluphenazine, haloperidol, loxapine, perphenazine, pimozide, trifluoperazine) and atypical antipsychotics (e.g., aripiprazole, amisulpiride, clozapine, olanzapine).
Appetite suppressants/stimulantsBenzphetamine, diethylpropion, phentermine, phendimetrazine, sibutramine.
AnxiolyticsAlprazolam, chlordiazepoxide, clorazepate, diazepam, doxepin, hydroxyzine, lorazepam, meprobamate, oxazepam, prazepam.
BronchodilatorsAlbuterol, eformoterol, ipratropium, metaproterenol, pirbuterol, salbutamol, salmeterol, tiotropium, umeclidinium.
Cardiovascular agentsAtenolol, clonidine, metoprolol, prazosin.
Muscle relaxantsBaclofen, cyclobenzaprine, orphenadrine.
Table
Table 2. Systemic diseases associated with xerostomia.
Table 2. Systemic diseases associated with xerostomia.
Systemic Diseases
Sjögren’s syndrome
Systemic lupus erythematosus
Diabetes (type 1 and type 2)
Viral infection (e.g., human immunodeficiency virus, hepatitis C virus, and human T-lymphotropic virus type 1)
End-stage renal disease
Primary biliary cirrhosis
Ectodermal dysplasia
Graft-versus-host disease
Sarcoidosis
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Kim, Y.-J. Xerostomia and Its Cellular Targets. Int. J. Mol. Sci. 2023, 24, 5358. https://doi.org/10.3390/ijms24065358

AMA Style

Kim Y-J. Xerostomia and Its Cellular Targets. International Journal of Molecular Sciences. 2023; 24(6):5358. https://doi.org/10.3390/ijms24065358

Chicago/Turabian Style

Kim, Yoon-Jung. 2023. "Xerostomia and Its Cellular Targets" International Journal of Molecular Sciences 24, no. 6: 5358. https://doi.org/10.3390/ijms24065358

APA Style

Kim, Y. -J. (2023). Xerostomia and Its Cellular Targets. International Journal of Molecular Sciences, 24(6), 5358. https://doi.org/10.3390/ijms24065358

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop