Abstract
Salivary glands secrete saliva, a mixture of proteins and fluids, which plays an extremely important role in the maintenance of oral health. Loss of salivary secretion causes a dry mouth condition, xerostomia, which has numerous deleterious consequences including opportunistic infections within the oral cavity, difficulties in eating and swallowing food, and problems with speech. Secretion of fluid by salivary glands is stimulated by activation of specific receptors on acinar cell plasma membrane and is mediated by an increase in cytosolic [Ca2+] ([Ca2+]i). The increase in [Ca2+]i regulates a number of ion channels and transporters that are required for establishing an osmotic gradient that drives water flow via aquaporin water channels in the apical membrane. The Store-Operated Ca2+ Entry (SOCE) mechanism, which is regulated in response to depletion of ER-Ca2+, determines the sustained [Ca2+]i increase required for prolonged fluid secretion. Core components of SOCE in salivary gland acinar cells are Orai1 and STIM1. In addition, TRPC1 is a major and non-redundant contributor to SOCE and fluid secretion in salivary gland acinar and ductal cells. Other TRP channels that contribute to salivary flow are TRPC3 and TRPV4, while presence of others, including TRPM8, TRPA1, TRPV1, and TRPV3, have been identified in the gland. Loss of salivary gland function leads to dry mouth conditions, or xerostomia, which is clinically seen in patients who have undergone radiation treatment for head-and-neck cancers, and those with the autoimmune exocrinopathy, Sjögren’s syndrome (pSS). TRPM2 is a unique TRP channel that acts as a sensor for intracellular ROS. We will discuss recent studies reported by us that demonstrate a key role for TRPM2 in radiation-induced salivary gland dysfunction. Further, there is increasing evidence that TRPM2 might be involved in inflammatory processes. These interesting findings point to the possible involvement of TRPM2 in Sjögren’s Syndrome, although further studies will be required to identify the exact role of TRPM2 in this disease.
Highlights
Salivary glands secrete fluid composed of water and electrolytes in response to neurotransmitter stimulation of plasma membrane receptors that cause an elevation of cytosolic [Ca2+ ] ([Ca2+ ]i ) in acinar cells, which are the primary site of fluid secretion [1,2,3] (Figure 1)
Studies done over the past 30 years have provided a tremendous amount of information about the key molecular components that regulate salivary gland fluid secretion, including those involved in
Such studies should provide novel targets and strategies for treatment. On such target in salivary glands is TRPM2, which appears to be critically involved in radiation-induced irreversible loss of salivary gland fluid secretion
Summary
Salivary glands secrete fluid composed of water and electrolytes in response to neurotransmitter stimulation of plasma membrane receptors that cause an elevation of cytosolic [Ca2+ ] ([Ca2+ ]i ) in acinar cells, which are the primary site of fluid secretion [1,2,3] (Figure 1). Channels involved in SOCE in salivary gland cells are Orai and TRPC1. Several different studies have demonstrated that TRPC1 is an essential channel for salivary gland function, where loss of the channel causes significant loss of fluid secretion and SOCE [17,18,19]. An extensive search for the molecular components of SOCE led to the identification of the transient receptor potential (TRP) superfamily of cation channels. These channels are expressed in a variety of organisms, including worms, flies, zebrafish, mice, and humans, and are broadly divided into two groups based on sequence and topological similarities. The physiologic roles and activation mechanisms regulating thermoTRP channels have been summarized in several comprehensive reviews [69,70,71]
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