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Phospholamban regulation of bladder contractility: evidence from gene-altered mouse models

Koji Nobe *, Roy L. Sutliff *, Evangelia G. Kranias *† and Richard J. Paul *†

1. Phospholamban (PLB) is an inhibitor of the sarcoplasmic reticulum (SR) Ca²⁺-ATPase (SERCA). Its presence and/or functional significance in contractility of bladder, a smooth muscle tissue particularly dependent on SR function, is unknown. We investigated this by measuring the effects of carbachol (CCh) on force and [Ca²⁺]_i in bladder from mice in which the PLB gene was ablated (PLB-KO mice). In the PLB-KO bladder, the maximum increases in [Ca²⁺]_i and force were significantly decreased (41.5 and 47.4 % of WT), and the EC₅₀ values increased.
2. Inhibition of SERCA with cyclopiazonic acid (CPA) abolished these differences between WT and PLB-KO bladder, localizing the effects to the SR.
3. To determine whether these effects were specific to PLB, we generated mice with smooth-muscle-specific expression of PLB (PLB-SMOE mice), using the SMP8 -actin promoter. Western blot analysis of PLB-SMOE mice showed approximately an eightfold overexpression of PLB while SERCA was downregulated 12-fold.
4. In PLB-SMOE bladders, in contrast, the response of [Ca²⁺]_i and force to CCh was significantly increased and the EC₅₀ values were decreased. CPA had little affect on the CCh-induced increases in [Ca²⁺]_i and force in PLB-SMOE bladder.
5. These results show that alteration of the PLB:SERCA ratio can significantly modulate smooth muscle [Ca²⁺]_i. Importantly, our data show that PLB can play a major role in modulation of bladder contractility.

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