Histamine H1 Receptor Induces Cytosolic Calcium Increase and Aquaporin Translocation in Human Salivary Gland Cells

Abstract

One of the common side effects of antihistamine medicines is xerostomia (dry mouth). The current consensus is that antihistamine-induced xerostomia comes from an antimuscarinic effect. Although the effect of antihistamines on salivary secretion is both obvious and significant, the cellular mechanism whereby this happens is still unclear because of the lack of knowledge of histamine signaling in human salivary glands. Here, we have studied histamine receptors and the effect of antihistamines on human submandibular acinar cells. In primary cultured human submandibular gland and a HSG cell line, histamine increased the intracellular Ca 2ϩ concentration. The histamine-induced cytosolic free Ca 2ϩ concentration ([Ca 2ϩ ] i ) increase was inhibited by histamine H1 receptor-specific antagonists, and the expression of the functional histamine H1 receptor was confirmed by reverse transcription-polymerase chain reaction. Interestingly, histamine pretreatment did not inhibit a subsequent carbachol-induced [Ca 2ϩ ] i rise without "heterologous desensitization." Chlorpheniramine inhibited a carbachol-induced [Ca 2ϩ ] i increase at a 100-fold greater concentration than histamine receptor antagonism, whereas astemizole and cetrizine showed more than 1000-fold difference, which in part explains the xerostomia-inducing potency among the antihistamines. Notably, histamine resulted in translocation of aquaporin-5 to the plasma membrane in human submandibular gland cells and green fluorescent proteintagged aquaporin-5 expressing HSG cells. We found that histidine decarboxylase and the histamine H1 receptor are broadly distributed in submandibular gland cells, whereas choline acetyltransferase is localized only at the parasympathetic terminals. Our results suggest that human salivary gland cells express histamine H1 receptors and histamine-synthesizing enzymes, revealing the cellular mechanism of antihistamineinduced xerostomia.

Activation of muscarinic receptors in rat parotid acinar cells induces AQP5 trafficking to nuclei and apical plasma membrane

“…In nuclei, AQP5 may be triggered to facilitate water transport across the nuclear membrane. Enhancement of [Ca 2+ ]i-induced trafficking of AQP5 is observed in eccrine sweat glands [18], submandibular glands [17,61] and human salivary gland cells [62]. The enhancement of c-APM-induced trafficking of AQP5 is seen in Brunner's glands [63,64] and lung epithelial cells [65].…”

Histamine modulates salivary secretion and diminishes the progression of periodontal disease in rat experimental periodontitis

“…Furthermore, previous studies have demonstrated the presence of histamine H1 and H2 receptor subtypes in rat SMG [31,48,49]. Histamine treatment also induces the translocation of aquaporin-5, which modulates water secretion to produce primary saliva, to the plasma membrane in human SMG cells through the histamine H1 receptor [31].…”

“…Furthermore, previous studies have demonstrated the presence of histamine H1 and H2 receptor subtypes in rat SMG [31,48,49]. Histamine treatment also induces the translocation of aquaporin-5, which modulates water secretion to produce primary saliva, to the plasma membrane in human SMG cells through the histamine H1 receptor [31]. In this regard, histamine H1 receptor antagonists prescribed for allergic reactions are reported to cause xerostomia (dry mouth), which is a pathological condition characterized by decreased salivary secretion [50].…”

“…Histamine [2-(4-imidazolyl)-ethylamine] is an endogenous biogenic amine widely distributed throughout the organism and it has long been known to be a pleiotropic mediator in different (patho)physiological conditions [27,28]. It has been previously reported that histamine could act as a stimulator of salivary secretion in SMG of cats and dogs [29,30], and, furthermore, histamine treatment induces the translocation of aquaporin-5, which modulates water secretion to produce primary saliva, to the plasma membrane in human SMG cells [31].…”

Protective Effect of Dendrobium officinale Polysaccharides on Experimental Sjogren's Syndrome

“…Clear evidence by fluorescence microscopy method also showed the up-regulation effect of DP on AQP5 in vitro test (Fig.2). Probably, such neural modulation as the role DP might play as the agonist of muscarinic acetylcholine receptor to increase the expression of AQP5 (Kim, Park et al 2009). …”