Herein, we demonstrated by Ussing chamber technique that male mice administered 1 g/kg 1,25(OH) 2D3 sc daily for 3 days exhibited increased duodenal calcium absorption, which was abolished by concurrent intravenous injection of recombinant mouse FGF-23. This FGF-23 administration had no effect on the background epithelial electrical properties, i.e., short-circuit current, transepithelial potential difference, and resistance. Immunohistochemical evidence of protein expressions of FGFR isoforms 1-4 in mouse duodenal epithelial cells suggested a possible direct effect of FGF-23 on the intestine. This was supported by the findings that FGF-23 directly added to the serosal compartment of the Ussing chamber and completely abolished the 1,25(OH) 2D3-induced calcium absorption in the duodenal tissues taken from the 1,25(OH) 2D3-treated mice. However, direct FGF-23 exposure did not decrease the duodenal calcium absorption without 1,25(OH) 2D3 preinjection. The observed FGF-23 action was mediated by MAPK/ERK, p38 MAPK, and PKC. Quantitative real-time PCR further showed that FGF-23 diminished the 1,25(OH) 2D3-induced upregulation of TRPV5, TRPV6, and calbindin-D 9k, but not PMCA1b expression in the duodenal epithelial cells. In conclusion, besides being a phosphatonin, FGF-23 was shown to be a novel calcium-regulating hormone that acted directly on the mouse intestine, thereby compromising the 1,25(OH) 2D3-induced calcium absorption.calbindin-D 9k; fibroblast growth factor receptor; Klotho; transient receptor potential vanilloid type 6; Ussing chamber FIBROBLAST GROWTH FACTOR (FGF)-23 has been recognized as the osteoblast/osteocyte-derived phosphate-regulating hormone, a phosphatonin with phosphaturic and hypophosphatemic action (19,42,45 (29). Some hereditary and acquired diseases, e.g., autosomal dominant hypophosphatemic rickets/osteomalacia, tumor-induced osteomalacia, and X-linked hypophosphatemic rickets, result from abnormally high circulating FGF-23 activity. Dysregulation of FGF-23 action is also evident in various pathological conditions, such as chronic metabolic acidosis and chronic kidney disease (11,20).Once secreted from osteoblasts and osteocytes, FGF-23 exerts its phosphaturic action in the renal proximal tubular cells via the FGF receptor (FGFR)/Klotho coreceptor complex, thereby downregulating Na ϩ -dependent phosphate transporter (NPT)-2a and NPT-2c expression (14). Its intracellular signaling in renal epithelial cells is conveyed through a number of pathways, e.g., mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), p38 MAPK, phosphoinositide 3-kinase (PI3K)/Akt, and protein kinase C (PKC) (12,13,43). FGF-23 also downregulates renal 25-hydroxyvitamin D 1␣-hydroxylase (1-OHase; also known as Cyp27b1) and upregulates 24-hydroxylase (24-OHase, Cyp24a1), which are important enzymes for production and inactivation of 1,25(OH) 2 D 3 , respectively, thereby reducing circulating levels of 1,25(OH) 2 D 3 (35, 42). Since 1,25(OH) 2 D 3 is the cardinal regulator of intestinal cal...

Key points Functional disorders (i.e. interstitial cystitis/painful bladder syndrome and irritable bowel syndrome) are associated with hyperexcitability of afferent nerves innervating the urinary tract and the bowel, respectively. Various non‐5‐HT3 receptor mRNA transcripts are expressed in mouse urothelium and exert functional responses to 5‐HT. Whilst 5‐HT3 receptors were not detected in mouse urothelium, 5‐HT3 receptors expressed on bladder sensory neurons plays a role in bladder afferent excitability both under normal conditions and in a mouse model of chronic visceral hypersensitivity. These data suggest that the role 5‐HT3 receptors play in bladder afferent signalling warrants further study as a potential therapeutic target for functional bladder disorders. Abstract Serotonin (5‐HT) is an excitatory mediator that in the gastrointestinal (GI) tract plays a physiological role in gut–brain signalling and is dysregulated in functional GI disorders such as irritable bowel syndrome (IBS). Patients suffering from IBS frequently suffer from urological symptoms characteristic of interstitial cystitis/painful bladder syndrome, which manifests due to cross‐sensitization of shared innervation pathways between the bladder and colon. However, a direct modulatory role of 5‐HT in bladder afferent signalling and its role in colon–bladder neuronal crosstalk remain elusive. The aim of this study was to investigate the action of 5‐HT on bladder afferent signalling in normal mice and mice with chronic visceral hypersensitivity (CVH) following trinitrobenzenesulfonic acid‐induced colitis. Bladder afferent activity was recorded directly using ex vivo afferent nerve recordings. Expression of 14 5‐HT receptor subtypes, the serotonin transporter (SERT) and 5‐HT‐producing enzymes was determined in the urothelium using RT‐PCR. Retrograde labelling of bladder‐projecting dorsal root ganglion neurons was used to investigate expression of 5‐HT3 receptors using single cell RT‐PCR, while sensory neuronal and urothelial responses to 5‐HT were determined by live cell calcium imaging. 5‐HT elicited bladder afferent firing predominantly via 5‐HT3 receptors expressed on afferent terminals. CVH animals showed a downregulation of SERT mRNA expression in urothelium, suggesting increased 5‐HT bioavailability. Granisetron, a 5‐HT3 antagonist, reversed bladder afferent hypersensitivity in CVH mice. These data suggest 5‐HT exerts a direct effect on bladder afferents to enhance signalling. 5‐HT3 antagonists could therefore be a potential therapeutic target to treat functional bladder and bowel disorders.

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Fluoxetine, a selective serotonin reuptake inhibitor anti-depressant, causes undesirable side effects, including diarrhea and constipation. This research investigated the direct effects of fluoxetine at 0.001, 0.01, 0.1, 1, 10, and 100 µM on duodenal and proximal colonic tissue contractions. The investigation aimed to determine related mechanisms using an isolated mouse intestine model. Our study showed that fluoxetine at 0.001 μM increased the amplitude of contraction in colonic tissue but decreased the amplitude in duodenal tissue. The direct application of higher concentrations of fluoxetine (1, 10, and 100 µM) reduced the amplitude of contractions in proximal colonic tissue. Moreover, we found that the stimulatory effect of 0.001 µM fluoxetine on the tone of contractions could be prevented by pre-incubating the tissue in ondansetron and atropine. Our findings suggest that the inhibition of the effect of fluoxetine was mainly mediated via 5-HT3 receptors and muscarinic signaling. These findings might explain the conflicting gastrointestinal symptoms caused by fluoxetine.