Background: FKBP12.6 is a crucial calcium regulatory molecule involved in the regulation of bladder excitatory contraction. This study employed FKBP12.6 knockout mice to investigate the impact of FKBP12.6 on the expression and function of IP3R/TRPM4 and its subsequent effect on bladder contraction function.
Methods: The study selected 129S2/SvPasCrl and FKBP12.6 knockout mice and constructed a Partial Bladder Outlet Obstruction (PBOO) mouse model. GSE1595 data were utilized to analyze calcium signaling pathway changes. Void spot assays, urodynamic tests, and visceromotor response were employed to evaluate bladder function, while HE staining was used to assess bladder morphology. Immunofluorescence, co-immunoprecipitation, and Western blot techniques were employed to detect the localization, expression, and binding changes of FKBP12.6, Inositol-1,4,5 trisphosphate Receptor (IP3R), and TRPM4.
Results: FKBP12.6 was significantly downregulated in PBOO mice (0.9998±0.07 vs. 0.2911±0.04; p <0.05). The micturition frequency (31.42±4.93 vs. 12.17±3.186), bladder sensitivity (1.59 ± 0.22 vs. 3.57± 0.43; p<0.01), detrusor instability, and muscle strip sensitivity (3.470.51 vs. 5.77±0.35; p<0.01) were increased significantly in FKBP12.6 Knockout (KO) mice (p <0.05). FKBP12.6 knockout did not affect the expressions of IP3R and TRPM4 proteins, but FKBP12.6 directly bound to IP3R in mouse bladder detrusor. IP3R/TRPM4 pathway inhibitors, 2-APB and 9-PHE, notably inhibited detrusor sensitivity, micturition frequency, and urination urgency in FKBP12.6 KO mice.
Conclusion: The expression of FKBP12.6 was decreased in the bladder of PBOO mice, and the deletion of FKBP12.6 may lead to bladder dysfunction in mice by affecting the functional activity of IP3R/TRPM4.
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