Functional Vanilloid Receptor-1 in Human Submandibular Glands

Ding, Qianwen; Zhang, Y.; Wang, Y.; Wang, Y.N.; Zhang, L.; Ding, Chong; Wu, Li‐Ling; Yu, Guang‐Yan

doi:10.1177/0022034510366841

Cited by 29 publications

(33 citation statements)

References 29 publications

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“…1,2 To date, most studies referring to the SMG secretion focus on the transcellular route through aquaporin channels, 14,15,29 whereas only a few studies focus on the paracellular pathway. 30,31 As the basic structure of the paracellular pathway, TJ is a multi-protein complex consisting of transmembrane proteins and intracellular scaffold proteins.…”

Section: Discussionmentioning

confidence: 99%

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Activation of transient receptor potential vanilloid subtype 1 increases expression and permeability of tight junction in normal and hyposecretory submandibular gland

Cong

Zhang

Shi

et al. 2012

Laboratory Investigation

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Tight junction (TJ) is an important structure that regulates material transport through the paracellular pathway across the epithelium, but its significance in salivary physiology and pathogenesis of salivary dysfunctional diseases is not fully understood. We previously demonstrated that a functional transient receptor potential vanilloid subtype 1 (TRPV1) expresses in submandibular gland (SMG). However, association of TRPV1-induced saliva secretion with TJ remains unknown. Here we explored the effect of TRPV1 activation on expression and function of TJ of rabbit SMG in vitro and in vivo. RT-PCR and western blot analysis revealed that capsaicin upregulated expression of zonula occludin-1 (ZO-1), claudin (Cldn)-3, and -11, but not Cldn-1, -2, -4, -5, and -7 in cultured SMG cells. Capsaicin also increased the entering of 4 kDa FITC-dextran into the acinar lumen, induced redistribution of cytoskeleton F-actin under confocal microscope, and these effects were abolished by preincubation of capsazepine, a TRPV1 antagonist, indicating that activation of TRPV1 increases expression and permeability of TJ in SMG. Additionally, in a hyposecretory model induced by rabbit SMG transplantation, the expression of ZO-1, Cldn-3, and -11 was decreased, whereas other TJs remained unaltered. The structure of TJ was impaired and the width of apical TJs was reduced under transmission electron microscope, concomitant with diminished immunofluorescence of F-actin in peri-apicolateral region, indicating impaired TJ expression and decreased paracellular permeability in the transplanted SMG. Moreover, topical capsaicin cream increased secretion, decreased TJ structural injury, reversed TJ expression levels, and protected F-actin morphology from disarrangement in transplanted SMGs. These data provide the first evidence to demonstrate that TJ components, particularly ZO-1, Cldn-3, and -11 have important roles in secretion of SMG under both physiological and pathophysiological conditions. The injury in TJ integrity was involved in the hypofunctional SMGs, and TRPV1 might be a potential target to improve saliva secretion through modulating expression and function of TJs. (2012) 92, 753-768; doi:10.1038/labinvest.2012 published online 5 March 2012 KEYWORDS: extracellular signal-regulated kinase 1/2; myosin light chain-2; saliva secretion; submandibular gland; tight junction; transient receptor potential vanilloid subtype 1 Tight junctions (TJs) are cell-cell interactions ubiquitously expressed in epithelium and endothelium, having an essential role in regulating water and solute transport through the paracellular pathway. 1 As a multifunctional protein complex, TJs are composed of transmembrane proteins, like claudin (Cldn) family members, and intracellular scaffold proteins, such as zonula occludin-1 (ZO-1), which link the transmembrane TJ proteins with intracellular actin Laboratory Investigation

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Section: Discussionmentioning

confidence: 99%

“…13 Our previous study demonstrated that TRPV1 is expressed in both human and rabbit SMGs, and TRPV1 activation by capsaicin increases saliva secretion. 14,15 These results indicate that activation of TRPV1 may be part of a novel pathway for regulating SMG secretion. However, the exact secretory mechanism mediated by TRPV1 is not fully understood.…”

mentioning

confidence: 82%

Activation of transient receptor potential vanilloid subtype 1 increases expression and permeability of tight junction in normal and hyposecretory submandibular gland

Cong

Zhang

Shi

et al. 2012

Laboratory Investigation

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“…Activation of the peripheral TRPV1 mediates Ca 2+ entry and increases cytosolic Ca 2+ concentration, thereby eliciting diverse physiological functions other than nociceptive transduction. We previously demonstrated that TRPV1 is expressed in both human and rabbit SMG cells, and TRPV1 activation by capsaicin induces saliva secretion (Zhang et al, 2006;Ding et al, 2010). We also found that capsaicin increases paracellular permeability of rabbit SMGs (Cong et al, 2012), suggesting that the salivation induced by capsaicin is, at least in part, by increasing paracellular transport.…”

Section: Introductionmentioning

confidence: 76%

“…We previously demonstrated that a functional TRPV1 is expressed in human and rabbit SMGs, and capsaicin-induced salivation partially involves an increased paracellular transport in rabbit SMGs (Zhang et al, 2006;Ding et al, 2010;Cong et al, 2012). However, the precise mechanism involved in TRPV1-modulated tight-junction barrier was still unknown.…”

Section: Discussionmentioning

confidence: 99%

Occludin is required for TRPV1-modulated paracellular permeability in the submandibular gland

Cong

Zhang

Yang

et al. 2013

Journal of Cell Science

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SummaryOccludin plays an important role in maintaining tight junction barrier function in many types of epithelia. We previously reported that activation of transient receptor potential vanilloid subtype 1 (TRPV1) in rabbit submandibular gland promoted salivary secretion, partly by an increase in paracellular permeability. We have now explored the role of occludin in TRPV1-modulated paracellular permeability in a rat submandibular gland cell line SMG-C6. Both TRPV1 and occludin were expressed in SMG-C6 cells, and capsaicin induced redistribution of occludin, but not claudin-3, claudin-4 or E-cadherin, from the cell membrane into the cytoplasm. Capsaicin also decreased transepithelial electrical resistance (TER) and increased the Trypan Blue and FITC-dextran flux. Capsazepine (CPZ), a TRPV1 antagonist, inhibited the capsaicin-induced occludin redistribution and TER decrease. Moreover, occludin knockdown by shRNA suppressed, whereas occludin re-expression restored, the TER response to capsaicin. Mechanistically, TRPV1 activation increased ERK1/2 and MLC2 phosphorylation. PD98059, an ERK1/2 kinase inhibitor, abolished the capsaicin-induced MLC2 phosphorylation, whereas ML-7, an MLC2 kinase inhibitor, did not affect ERK1/2 phosphorylation, suggesting that ERK1/2 is the upstream signaling molecule of MLC2. Capsaicin also induced F-actin reorganization, which was abolished by CPZ, PD98059 and ML-7, indicating that TRPV1 activation altered F-actin organization in an ERK1/2-and MLC2-dependent manner. Furthermore, either PD98059 or ML-7 could abolish the capsaicin-induced TER response and occludin redistribution, whereas knockdown of ERK1/2 further confirmed that the TRPV1-modulated paracellular permeability was ERK1/2 dependent. Taken together, these results identified a crucial role of occludin in submandibular epithelial cells, and more importantly, demonstrated that occludin was required to mediate TRPV1-modulated paracellular permeability.

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“…Although the VR1 was found previously in neural cells, recent evidence suggests that functional VR1 is expressed in nonneuronal cells such as the epithelial cells, glial cells, skeletal muscle cells, and submandibular glands (Birder et al 2001;Inoue et al 2002;Doly et al 2004;Tóth et al 2005;Xin et al 2005;Kim et al 2006;Ding et al 2010).…”

Section: Introductionmentioning

confidence: 98%

Cell-type specific expression of vanilloid receptor 1 in the taste cells of rat circumvallate papillae

Moon¹,

Han²,

Kang³

2011

Animal Cells and Systems

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The present study demonstrates the first-ever characterization of cell types that express the vanilloid receptor 1 (VR1) in the taste buds of rat circumvallate papillae. We performed electron microscopy to identify the subcellular location. The VR1 immunoreactivity was associated with the endoplasmic reticulum, cytoplasmic vesicles, and plasma membrane of taste cells. These results demonstrate the localization of the VR1 in membranous structures of the taste cells. We used double immunofluorescence histochemistry with taste cell type-specific markers to identify the cell types that express the VR1. The VR1 was detected in all functional taste cell types (Type I, Type II, and Type III cells). Together, our data suggest that the VR1 might play different roles according to the cell types within a taste bud.

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Functional Vanilloid Receptor-1 in Human Submandibular Glands

Cited by 29 publications

References 29 publications

Activation of transient receptor potential vanilloid subtype 1 increases expression and permeability of tight junction in normal and hyposecretory submandibular gland

Activation of transient receptor potential vanilloid subtype 1 increases expression and permeability of tight junction in normal and hyposecretory submandibular gland

Occludin is required for TRPV1-modulated paracellular permeability in the submandibular gland

Cell-type specific expression of vanilloid receptor 1 in the taste cells of rat circumvallate papillae

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