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J Dent Res 82(6): 476-480, 2003
© 2003 International and American Associations for Dental Research

RESEARCH REPORT
Biological

Age-related Decreases in the Response of Aquaporin-5 to Acetylcholine in Rat Parotid Glands

N. Inoue, H. Iida, Z. Yuan, Y. Ishikawa*, and H. Ishida

Department of Pharmacology, Tokushima University School of Dentistry, Kuramoto-cho, Tokushima 770-8504, Japan;

*corresponding author, isikawa{at}dent.tokushima-u.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Aquaporin-5 (AQP5) is important in salivary fluid secretion in response to cholinergic and adrenergic stimuli in rat parotid glands. We hypothesized that expression and function of AQP5 might change with age. Acetylcholine and epinephrine induced increases in AQP5 levels in the apical plasma membranes of both young adult and senescent rats. The stimulatory effect of acetylcholine, but not that of epinephrine, on AQP5 levels in the apical plasma membranes of the cells decreased markedly during aging. The quinuclidine derivative, SNI-2011, induced a persistent increase in AQP5 levels in the apical plasma membrane in the cells of both these rats. The amounts of M3-muscarinic receptor and Gq proteins did not decrease during aging. The age-related alteration in the responsiveness of AQP5 in the cells to these stimuli might account for the concomitant changes in nitric oxide synthase activity. These results suggest that SNI-2011 might have therapeutic benefit for the treatment of age-related xerostomia.

KEY WORDS: aging • parotid gland • aquaporin-5 • acetylcholine • nitric oxide


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Xerostomia is characterized by oral dryness and difficulty in the performance of oral functions (Mandel, 1987). This condition can result from the intake of xerogenic drugs, therapeutic irradiation, or systemic diseases (Bergdahl and Bergdahl, 2000). The stimulatory effects of various agonists on salivary secretion also decrease with age. Pilocarpine-stimulated parotid saliva flow rate is approximately 50% lower in aged animals compared with young adult rats (Bodner and Baum, 1985). Several members of the aquaporin (AQP) family of proteins, which form channels that selectively transport water across the plasma membrane, have been identified and their cDNAs cloned from a variety of mammalian tissues (King and Agre, 1996; Ishibashi et al., 2000). The cDNA for AQP5 was cloned from salivary glands (Raina et al., 1995). Salivary fluid secretion is defective in transgenic mice lacking AQP5, indicating that AQP5 is important in salivary gland function (Ma et al., 1999; Krane et al., 2001). Acetylcholine and epinephrine acting at the M3-muscarinic receptor (M3-mAChR) and {alpha}1-adrenergic receptor, respectively, on the basolateral plasma membrane (BLM) of parotid cells induce an increase in AQP5 levels in the apical plasma membrane (APM) of these cells (Ishikawa et al., 1998, 1999). Recently, we demonstrated that nitric oxide (NO)/guanosine 3', 5'-cyclic monophosphate (cGMP) signal transduction following activation of M3-mAChR contributed to increased AQP5 levels in the APM of rat parotid glands via [Ca2+]i homeostasis (Ishikawa et al., 2002a).

The purpose of the present experiment was to examine changes in the responsiveness of AQP5 in rat parotid tissues to neurotransmitters during aging. In this study, we found that the responsiveness of AQP5 in rat parotid tissues to acetylcholine decreased more markedly during aging than that to epinephrine and that the quinuclidine derivative, SNI-2011, improved age-related xerostomia.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Preparation and Incubation of Rat Parotid Tissues
Male Wistar rats [10-week-old (young adult) and 115-week-old (senescent) rats] were provided with laboratory chow (MF; Oriental Yeast, Tokyo, Japan) and water ad libitum, and maintained in a temperature-controlled environment (22 ± 2°C) with a 12-hour light/dark cycle (lights on at 0600 hrs). All procedures were approved by the animal care committee of Tokushima University Dental School. Parotid glands were removed and transferred to ice-cold Krebs-Ringer Tris (KRT) solution [120 mmol/L NaCl, 4.8 mmol/L KCl, 1.2 mmol/L KH2PO4, 1.2 mmol/L MgSO4, 1.0 mmol/L CaCl2, 16 mmol/L Tris-HCl (pH 7.4), 5 mmol/L glucose] that had been aerated with O2 gas. Tissue slices (0.4 mm thick) were equilibrated with KRT solution and then incubated at 37°C in KRT solution in the presence or absence of acetylcholine or other agents as described previously (Ishikawa et al., 2002b).

Preparation of APM and BLM Fractions of Rat Parotid Tissues
The APM fraction was prepared from rat parotid tissues as described previously (Ishikawa et al., 1998). Briefly, the filtrate of the homogenate of the tissue slices was centrifuged at 35,000 x g for 30 min, and the resultant precipitate was suspended in 5 mmol/L HEPES buffer (pH 7.5) containing 50 mmol/L mannitol and 0.25 mmol/L MgCl2. After the addition of MgCl2 to give a final concentration of 10 mmol/L, the suspension was incubated on ice for 30 min while being stirred and was then centrifuged at 3000 x g for 15 min for precipitation of BLM. The resultant supernatant was again centrifuged at 35,000 x g for 30 min for precipitation of APM.

Preparation of Antibodies to AQP5
Rabbit polyclonal antibodies to AQP5 were generated in response to a synthetic peptide (KGTYEPEEDWEDHREERKKTI), which corresponded to the deduced COOH-terminal amino acid sequence of AQP5 (Raina et al., 1995).

Western Blot Analysis of AQP5, M3-mAChR, and Gq/11{alpha} Proteins
The APM fraction was subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) in 12.5% polyacrylamide gels, and the separated proteins were electrophoretically transferred to a nitrocellulose transfer membrane (Hybond ECL, Amersham, Buckinghamshire, UK) by means of a Trans-Blot apparatus (Bio-Rad, Hercules, CA, USA). The blots were probed with antibodies to AQP5, M3-mAChR (Biogenesis Ltd, Poole, Dorset. England), or Gq/11{alpha} (Calbiochem-Novabiochem Co., Darmstadt, Germany). Immunodetection was performed according to the enhanced chemiluminescence method (Amersham).

Ligand Binding Assay
[3H]Quinuclidinyl benzilate (QNB) binding was assayed by the method of Gadbut and Galper (1994).

Measurement of Nitric Oxide Synthase (NOS) Activity in Parotid Acinar Cells
Rat parotid acinar cells were isolated by collagenase and hyaluronidase digestion as described previously (Ishikawa et al., 2002b) and incubated in RPM1 1640 with 10 µmol/L 4,5-diamino-fluorescein/diacetate (DAF-2/DA) for 30 min at 37°C, then aerated with 95% O2/5% CO2 at pH 7.4. Acinar cells were suspended in a HEPES-buffered Krebs-Ringer bicarbonate medium containing 118.5 mmol/L NaCl, 4.7 mmol/L KCl, 1.2 mmol/L KH2PO4, 1.0 mmol/L CaCl2, 1.2 mmol/L MgSO4, 24.9 mmol/L NaHCO3, and 5.0 mmol/L HEPES (pH 7.4), and NOS activity was then measured by a fluorescence study as described (Tritsaris et al., 2000). The cells were gently stirred in a cuvette maintained at 37°C with or without acetylcholine and other agents as indicated. Changes in the fluorescence generated by reaction of DAF-2/DA with NO were monitored with a fluorescence spectrometer (CF-4000, Hitachi, Tokyo, Japan). The experiments were performed with an excitation wavelength of 495 nm and an emission wavelength of 515 nm.

Statistics
All data were expressed as the mean value ± standard error (SE) and were tested for statistical significance by Student’s t test. Values of P less than 0.05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Age-associated Difference in Total AQP5, M3-mAChR, and Gq/11{alpha} Protein Levels in Rat Parotid Glands
The AQP5 levels in the parotid tissue homogenate were slightly increased in senescent rats in comparison with young adult rats (% of control, 135 ± 6; Fig. 1AGo, lanes 5, 6). Treatment of the parotid tissues from young adult and senescent rats with 10 µM SNI-2011 for 10 min at 37°C did not change the AQP5 levels in the homogenate compared with non-treated tissues (Fig. 1AGo, lanes 1-4), showing that SNI-2011 did not affect total AQP5 levels in the tissues. The M3-mAChR (Fig. 1BGo) and Gq/11{alpha} protein (Fig.1CGo) levels in parotid tissues from young adult rats were similar to those from senescent rats. The maximum binding sites of [3H]QNB in parotid tissues from young adult and senescent rats were 138.8 ± 9.2 and 121.5 ± 8.3 fmol/mg protein, respectively. The function of M3-mAChR did not show age-related difference in the tissues.



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  		Figure 1. Western blots for AQP5 in the homogenate and M3-muscarinic receptors and Gq/11{alpha} protein in basolateral membrane of parotid tissues. Parotid slices from 10-week-old (Young) or 115-week-old (Old) rats were incubated for 10 min at 37°C in the absence (1, 3, 5, 6) or presence (2, 4) of 10 µM SNI-2011. The homogenate (40 µg of protein) (A) and basolateral membrane (40 µg of protein) (B,C) of parotid glands from young adult (1, 2, 5) and senescent rats (3, 4, 6) were subjected to immunoblot analysis with antibodies (1:1500 dilution) to AQP5 (A), M3-mAChR (B), and Gq/11{alpha} (C).

 
Age-associated Difference in the Responses of AQP5 to Acetylcholine and Epinephrine in Rat Parotid Glands
The effects of 1 µM acetylcholine and 1 µM epinephrine on AQP5 levels in the APM were maximal at 15 sec and 1 min, respectively, as reported previously (Ishikawa et al., 1998, 1999). Treatment of parotid tissues from young adult rats with acetylcholine for 15 sec resulted in a marked (355 ± 41%) increase in AQP5 levels in the APM (Fig. 2Go). In contrast, identical treatment of parotid tissue from senescent rats induced only 180 ± 7% increase in the AQP5 levels in the APM. Incubation with epinephrine for 1 min increased AQP5 levels in the APM of parotid tissue from young adult rats by 233 ± 26% (Fig. 2Go). Identical treatment of parotid tissue from senescent rats induced a similar (175 ± 28%) increase in AQP5 in the APM. These results showed that the stimulatory effect of acetylcholine, but not that of epinephrine, on AQP5 levels in the APM of tissues decreased markedly during aging.




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  		Figure 2. Effects of acetylcholine and epinephrine on AQP5 levels in the apical plasma membrane of parotid tissues from senescent and young adult rats. (A) Parotid slices from 10-week-old (Young) or 115-week-old (Old) rats were incubated for 15 sec at 37°C in the absence (C) or presence (ACh) of 1 µM acetylcholine and 1 µM eserine or incubated for 1 min at 37°C in the absence (C) or presence (Epi) of 10 µM epinephrine. The apical plasma membrane fraction (5 µg of protein) was subjected to immunoblot analysis with anti-AQP5 antibody. (B) Immunoblots were subjected to densitometric analysis, and the amount of AQP5 was expressed as a percentage of the control cell values. Data are expressed as means ± SE of 6 independent experiments. **P < 0.01, ***P < 0.001 vs. the value of the control cells.

 
Effect of SNI-2011 on the AQP5 Levels in the APM of Parotid Tissues from Young Adult and Senescent Rats
SNI-2011 acting at M3-mAChRs induced a persistent increase in AQP5 levels in the APM of parotid tissues from young adult rats (Ishikawa et al., 2000). We therefore investigated the effect of this agent on parotid tissues from senescent rats. Whereas the increase in AQP5 levels in the APM of parotid tissues from young adult rats induced by 10 µM SNI-2011 was detectable at 1 min and maximal at 10 min, its effect on parotid tissues from senescent rats was not detectable at 1 min but was also maximal at 10 min (Fig. 3Go). The maximal increase in the abundance of AQP5 in the APM induced by SNI-2011 was smaller for parotid tissues from senescent rats (188 ± 7%) than for tissues from young adult rats (302 ± 13%). After incubation with SNI-2011 for 30 min, the AQP5 levels in the APM in the tissues of senescent rats (178 ± 16%) did not differ significantly from those of young adult rats (202 ± 18%). The AQP5 levels in the APM of parotid tissues from both senescent and young adult rats were still significantly increased at this time. These results indicate that SNI-2011 induces a persistent increase in the amount of AQP5 in the APM of parotid tissues not only in young adult rats but also in senescent rats.




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  		Figure 3. Time course of the effects of SNI-2011 and acetylcholine on the amount of AQP5 in the apical plasma membrane of parotid tissues from young adult and senescent rats. (A) Parotid slices from 10-week-old (Young) or 115-week-old (Old) rats were incubated at 37°C for 0, 1, 3, 10, or 30 min (lanes 1 to 5, respectively) in the presence of 10 µM SNI-2011. The apical plasma membrane fraction (5 µg of protein) was then subjected to immunoblot analysis with antibodies to AQP5. (B) Immunoblots were subjected to densitometric analysis, and the amount of AQP5 in 10-week-old ( O ) or 115-week-old ( • , solid line) rats was expressed as a percentage of the value for respective control tissues. Parotid slices from 115-week-old ( • , dotted line) rats were incubated at 37°C for 0, 0.25, 1, 3, or 10 min in the presence of 1 µM acetylcholine and 1 µM eserine. Data are means ± SE of values from 3 independent experiments performed with tissues from 3 different rats. *P < 0.05, **P < 0.01, ***P < 0.001 vs. the control value.

 
Age-associated Difference in the Responses to Acetylcholine and Epinephrine of NOS Activity in Dispersed Parotid Cells in Rats
The increase in AQP5 levels in the APM induced by the activation of M3-mAChR is mediated by an increase in cGMP formed through NO catalytic action on soluble guanyl cyclase (Ishikawa et al., 2002a). NOS activity was measured in isolated acinar cells from parotid glands of senescent and young adult rats (Fig. 4Go). Although acetylcholine stimulation of the cells from parotid tissues of young adult rats abruptly increased DAF-2/DA fluorescence, that of senescent rats increased only gradually (Fig. 4AGo). When the cells from senescent or young adult rats were stimulated with epinephrine, there were no significant differences in the fluorescence between these cells (Fig. 4BGo). Although SNI-2011 stimulation of the cells from both senescent and young adult rats gradually increased the fluorescence, the intensity of the fluorescence in the cells from senescent rats was lower than that from young adult rats (Fig. 4CGo).



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  		Figure 4. Effects of acetylcholine, epinephrine, and SNI-2011 on NOS activity in isolated parotid acinar cells from young adult or senescent rats. The isolated parotid acinar cells from 10-week-old (Young) or 115-week-old (Old) rats were pre-incubated with DAF-2/DA. Cells suspended with Krebs-Ringer bicarbonate solution were incubated with 1 µM acetylcholine(ACh) (A), 1 µM epinephrine (Epi) (B), and 10 µM SNI-2011 (C). The traces are representative of 3 independent experiments. Acetylcholine, epinephrine, and SNI-2011 were applied as indicated by the arrow. **P < 0.01, ***P < 0.001 vs. the control value.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, acetylcholine and epinephrine induced an increase in AQP5 levels in the APM of parotid tissues from senescent as well as young adult rats. Acetylcholine and epinephrine act at M3-mAChR (Ishikawa et al., 1998, 2002a) and {alpha}1-adrenergic receptor (Ishikawa et al., 1999), respectively, and induce the rapid and transient increase in AQP5 levels in the APM via the enhancement of [Ca2+]i. These findings suggest that senescent and young adult rats have the same responsiveness to Ca2+ to increase AQP5 levels in parotid tissues. Stimulation of muscarinic (Dai et al., 1991) and {alpha}1-adrenergic (Putney, 1986) receptors in rat parotid acini is coupled with hydrolysis of PIP2, IP3 generation and Ca2+ release from intracellular Ca2+ stores (Hughes et al., 1988). In general, IP3-gated channels release Ca2+, which would in turn induce Ca2+ release from the Ca2+-induced Ca2+ release pathway through ryanodine receptors (Berridge, 1993). Both IP3-sensitive and IP3-insensitive stores appear to have important roles in the mobilization of Ca2+ to the cytoplasm following stimulation by secretagogues. The increase in [Ca2+]i in salivary glands results in the rapid secretion of saliva (Foskett and Melvin, 1989). Although a defect in the activation of Gq/11{alpha} protein in parotid tissues from senescent rats was recognized (Sawaki et al., 1995), and the level of IP3 in parotid cells induced by {alpha}1-adrenergic agonists decreased with age (Ishikawa et al., 1988), age-dependent changes in the mobilization of Ca2+ to the cytoplasm from IP3-sensitive and IP3-insensitive stores have not been clarified. Acetylcholine increased AQP5 levels in APM by 3.6-fold in parotid tissues of young adult rats, but by only 1.8-fold in those of senescent rats (Fig. 2Go). In contrast, there was no significant difference in the epinephrine-induced increase in AQP5 levels in APM of parotid tissues between senescent and young adult rats (Fig. 2Go). This finding indicated a marked decrease in the responsiveness of AQP5 in the tissues of the senescent rats to cholinergic stimulation, but not to adrenergic stimulation. A difference in Ca2+ mobilization in rat parotid tissues during aging in response to adrenergic or cholinergic stimulation would also explain the age-associated differences in the responsiveness of AQP5 levels to these agonists.

In Ca2+-mediated intracellular signal transduction mechanisms, an increase in [Ca2+]i has an important role in the activation of Ca2+/calmodulin (CaM)-dependent proteins, such as CaM kinases, myosin light-chain kinase (MLCK), and NOS. CaM kinase II is a multifunctional enzyme required for both granule mobilization under stimulation conditions and maintenance of secretory capacity under control conditions in pancreatic ß-cells (Gromada et al., 1999). MLCK appears to be involved in Ca2+-dependent secretion of saliva and amylase (Ishikawa et al., 2002a,b). It has been known that NO activates guanyl cyclase, which produces cGMP that then activates protein kinase G (Lucas et al., 2000). Recently, we reported that NO/cGMP signal transduction has a crucial role in Ca2+ homeostasis in the M3-mAChR-stimulated increase in AQP5 levels in the APM of rat parotid glands (Ishikawa et al., 2002a). In the present study, we measured changes in NOS activity in response to acetylcholine, epinephrine, and SNI-2011 during aging (Fig. 4Go). The alteration in the responsiveness of AQP5 in rat parotid tissues to acetylcholine, epinephrine, and SNI-2011 during aging might account for the concomitant increase in NOS activity. Further investigation is necessary, however, to clarify age-associated changes in NOS activity.

Together, our results indicate that the stimulatory effect of acetylcholine, but not that of epinephrine, on AQP5 levels in the APM of rat parotid cells decreases markedly with age. The quinuclidine derivative SNI-2011 induced a persistent increase in the amount of AQP5 in the APM of parotid tissue, not only in young adult rats but also in senescent rats (Fig. 3Go). SNI-2011 improves cognitive deficits in a cholinergic lesion animal model without producing other central or peripheral cholinergic side-effects at the effective doses, and was suggested as a candidate drug for the treatment of Alzheimer’s disease (Gurwitz et al., 1994), cholinergic correlation of rhythmic slow neuronal spiking in the hippocampus, cholinergic induction in the long-term potentiation of synaptic efficacy, and memory (Iga et al., 1996). This drug might therefore prove therapeutically beneficial for the treatment of age-related xerostomia.


   ACKNOWLEDGMENTS
 
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Received June 24, 2002; Last revision March 12, 2003; Accepted March 18, 2003


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 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
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