Degradation of submandibular gland AQP5 by parasympathetic denervation of chorda tympani and its recovery by cevimeline, an M3 muscarinic receptor agonist

Li, Xuefei; Ahmad, Azlina; Karabasil, Mileva Ratko; Purwanti, Nunuk; Hasegawa, Takahiro; Yao, Chenjuan; Akamatsu, Tetsuya; Hosoi, Kazuo

doi:10.1152/ajpgi.00359.2007

Cited by 25 publications

(42 citation statements)

References 52 publications

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“…These findings imply that the AQP5 level as well as the SMG itself is strongly dependent on the parasympathetic nervous system. The findings of the previous study also implied the possibility that the reduction in AQP5 level is associated with degradation by the lysosomal system (32).…”

mentioning

confidence: 78%

“…Therefore, for further understanding, we previously studied the role of the autonomic nervous system on AQP5 regulation in the submandibular gland (SMG). A previous report from our laboratory (32) showed that parasympathetic denervation of the chorda tympani (CTD), but not sympathectomy, causes a decrease in SMG AQP5 expression to 37% of that of the contralateral gland at the 4th week after the operation. In addition, a 50% reduction in the SMG weight occurs compared with the weight of the contralateral gland in as short as 1 wk after the operation (32).…”

mentioning

confidence: 92%

“…A previous report from our laboratory (32) showed that parasympathetic denervation of the chorda tympani (CTD), but not sympathectomy, causes a decrease in SMG AQP5 expression to 37% of that of the contralateral gland at the 4th week after the operation. In addition, a 50% reduction in the SMG weight occurs compared with the weight of the contralateral gland in as short as 1 wk after the operation (32). These findings imply that the AQP5 level as well as the SMG itself is strongly dependent on the parasympathetic nervous system.…”

mentioning

confidence: 92%

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Roles of lysosomal proteolytic systems in AQP5 degradation in the submandibular gland of rats following chorda tympani parasympathetic denervation

Ahmad¹,

Javkhlan

Hiroshima³

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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Chorda tympani denervation (CTD) of rats was earlier shown to result in loss of submandibular gland (SMG) weight (at only 1 wk) and in continued reduction in aquaporin 5 (AQP5) protein expression (until 4 wk), without affecting its mRNA synthesis (Li X, Azlina A, Karabasil MR, Purwanti N, Hasegawa T, Yao C, Akamatsu T, Hosoi K. Am J Physiol Gastrointest Liver Physiol 295: G112-G123, 2008). The present study indicated that despite elevation of bax, a proapoptosis protein, by CTD, the operation also increased the level of bcl-2, an antiapoptosis protein, in the SMG. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL assay) showed no increase in the number of apoptotic cells in the SMG. CTD, however, induced strongly and transiently (at 1-3 days) the protein expression of LC3B-II, a marker protein of autophagosomes, suggesting that the reduction in the gland weight was due to onset of autophagy by CTD. Upon CTD, Lamp2, a lysosomal marker, gradually increased in amount, reaching a peak at the 14th day. Immunohistochemical analysis revealed an increase in the number of lysosome-like structures positive for both AQP5 and Lamp2 in the acinar cells of the SMG after CTD; similar changes were observed also for AQP5 and LC3Bs. These data suggest that AQP5 in the SMG entered autophagosomes and/or lysosomes for degradation upon CTD. In vitro AQP5-degrading activity was found in the SMG extracts, and such activity was shown to be increased by CTD. Inhibitor experiments implied cathepsins B and L to be candidate enzymes for this degradation under normal and CTD conditions, respectively.

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confidence: 78%

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confidence: 92%

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confidence: 92%

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Roles of lysosomal proteolytic systems in AQP5 degradation in the submandibular gland of rats following chorda tympani parasympathetic denervation

Ahmad¹,

Javkhlan

Hiroshima³

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…From normal and IPR-injected mice, the submandibular gland (SMG) and PG tissues were isolated, and the membrane fraction was prepared as described previously (11,31). Briefly, the SMG and PG tissues were homogenized in the ice-cold homogenization buffer (5 mM HEPES buffer, pH 7.5, containing 50 mM mannitol, 10 mM MgCl 2, 1 mM PMSF, 1 g/ml aprotinin, 2 g/ml pepstatin A, 2 g/ml leupeptin, and 1 tablet of complete EDTA-free protease inhibitor cocktail/25 ml of buffer) by using a glass mortar fitted with a Teflon pestle and centrifuged at 800 g for 10 min at 4°C to remove the nucleus and cell debris.…”

Section: Methodsmentioning

confidence: 99%

“…On the other hand, there was an 87% reduction in the content of AQP2 protein in inner medullary cells of the collecting duct, with no significant change in the AQP2 mRNA level in the dihydrotachysterol-induced hypercalcemia/hypercalciuria (23,25). Similarly, without affecting its mRNA level, chorda timpani denervation induces AQP5 degradation via the lysosomal system in the rat submandibular gland (2,11). These reports imply that the degradation system also plays important roles in regulation and/or control of the AQP function.…”

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confidence: 99%

Effects of isoproterenol on aquaporin 5 levels in the parotid gland of mice in vivo

Chen

Yao

Hasegawa

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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In the membrane fraction of mouse parotid gland (PG), the protein level of aquaporin 5 (AQP5), a member of the water channel family, was increased by injection (ip) of isoproterenol (IPR), a ␤-adrenergic agonist, at 1 h, and stayed at high levels until 6 h; this change occurred simultaneously as amylase secretion. The AQP5 level then decreased and returned toward the original level at 12-48 h. After IPR injection, the AQP5 mRNA gradually increased and reached a maximum at 24 h. The facts suggest a rapid appearance of AQP5 at plasma membrane by IPR and subsequent degradation/metabolism by activation of proteolytic systems. Pretreatment of animals with two calpain inhibitors, N-Ac-Leu-Leu-methininal (ALLM) and calpeptin, as well as a protein synthesis inhibitor, cycloheximide (CHX), significantly suppressed the IPR-induced AQP5 degradation in the PG membrane fraction; such suppression was not observed by two proteasome inhibitors, MG132 and lactacystin, or the lysosome denaturant chloroquine, although most of these inhibitors increased AQP5 protein levels in unstimulated mice. The AQP5 protein was also degraded by -calpain in vitro. Furthermore, we demonstrated that -calpain was colocalized with AQP5 in the acinar cells by immunohistochemistry, and its activity in the PG was increased at 6 h after IPR injection. These results suggest that the calpain system was responsible for IPR-induced AQP5 degradation in the parotid gland and that such a system was coupled to the secretory-restoration cycle of amylase in the PG. aquaporin 5; exocytosis; -calpain; parotid gland; isoproterenol AQUAPORINS (AQPs) are members of the water channel family that facilitate water movement between in and out of cells; they are expressed in various tissues and cells throughout the body and play pivotal roles in water movement. So far, 13 different AQPs (AQP 0 -12) have been identified in mammals (27). Among them, AQP5 is the one identified first in the salivary gland (24), and its deficiency in mice has been shown to lead to a decrease in their survival rates at the embryonic stage (9, 13). Studies of the AQP5-mutant rat (18) and AQP5-knockout mice (13) as well as the model mouse of Sjögren's syndrome (26) have indicated that AQP5 plays a pivotal role in maintaining the normal physiological function of the salivary gland; i.e., some of these animals produce significantly hypertonic, viscous, and smaller volumes of saliva (13, 18). The parotid gland (PG) belongs to one of the major salivary glands and expresses abundant AQP5 in the luminal membrane of its serous acinar cells (20, 31). It was reported previously that isolated and disaggregated PG acinar cells prepared from AQP5-knockout mice showed a significant decrease in transmembrane water transport (9). These results suggest that a certain quantity of fluid secreted by mouse salivary gland is due to the transcellular water transport, in which AQP5 plays a major role.Acinar cells of the PG in mice are filled with a plenty of secretory granules containing amylase, which contributes 80% o...

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Parasympathectomy increases resting secretion of the submandibular gland in minipigs in the long term

Zhang

Huang

Cong

et al. 2018

Journal Cellular Physiology

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Parasympathectomy leads to retrogressive alteration and dysfunction of the submandibular gland (SMG) within 1 month, but its long‐term effect is unclear. Excessive secretion is observed in half of the patients 4–6 months after SMG transplantation, which completely denervates the gland. Here, we investigated the long‐term effect of parasympathectomy on the secretion of SMGs in minipigs. The results showed that the resting salivary secretion of SMGs decreased by 82.9% of that in control at 2 months after denervation, but increased by 156% at 6 months. Although experiencing an atrophic period, the denervated glands regained their normal morphology by 6 months. The expression of the function‐related proteins, including muscarinic acetylcholine receptor (mAChR) 3, aquaporin 5 (AQP5), tight junction protein claudin‐3, and claudin‐4 was decreased at 2 months after denervation. Meanwhile, the protein expression of stem cell markers, including sex‐determining region Y‐box 2 and octamer‐binding transcription factor 4, and the number of Ki67+ cells were significantly increased. However, at 6 months after denervation, the expression of mAChR3, AQP5, claudin‐1, claudin‐3, and claudin‐4 was significantly raised, and the membrane distribution of these proteins was increased accordingly. The autonomic axonal area of the glands was reduced at 2 months after denervation but returned to the control level at 6 months, suggesting that reinnervation took place in the long term. In summary, parasympathectomy increases resting secretion of the SMGs in the long term with a possible mechanism involving improved transepithelial fluid transport. This finding may provide a new strategy for xerostomia treatment.

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Degradation of submandibular gland AQP5 by parasympathetic denervation of chorda tympani and its recovery by cevimeline, an M3 muscarinic receptor agonist

Cited by 25 publications

References 52 publications

Roles of lysosomal proteolytic systems in AQP5 degradation in the submandibular gland of rats following chorda tympani parasympathetic denervation

Roles of lysosomal proteolytic systems in AQP5 degradation in the submandibular gland of rats following chorda tympani parasympathetic denervation

Effects of isoproterenol on aquaporin 5 levels in the parotid gland of mice in vivo

Parasympathectomy increases resting secretion of the submandibular gland in minipigs in the long term

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