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.