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NK2 receptor mediated detrusor muscle contraction involves Gq/11-dependent activation of voltage-dependent calcium channels and the RhoA-Rho kinase pathway

Tachykinins (TKs) are involved both in the physiological regulation of urinary bladder functions and in the development of overactive bladder (OAB) syndrome. The aim of the present study was to investigate the signal transduction pathways of TKs in the detrusor muscle to provide potential pharmacological targets for the treatment of bladder dysfunctions related to enhanced TK production. Contraction force, intracellular Ca2+ concentration([Ca2+]ic) and RhoA activity were measured in mouse urinary bladder smooth muscle (UBSM). TKs and the NK2 receptor (NK2R) specific agonist [β-Ala⁸]-NKA(4-10) evoked contraction, which was inhibited by the NKR2 antagonist MEN10376. In Gαq/11 deficient mice [β-Ala⁸]-NKA(4-10)-induced contraction and [Ca2+]ic increase were abolished. Although Gq/11-proteins are linked principally to phospholipase C β (PLC-β) and inositol trisphosphate-mediated Ca2+ release from intracellular stores, we found that PLC-β inhibition and sarcoplasmic reticulum Ca2+ depletion failed to have any effect on contraction induced by [β-Ala⁸]-NKA(4-10). In contrast, lack of extracellular Ca2+ or blockade of voltage dependent Ca2+ channels (VDCC) suppressed contraction. Furthermore, [β-Ala⁸]-NKA(4-10) increased RhoA activity in the UBSM in a Gq/11-dependent manner and inhibition of Rho kinase (ROCK) with Y-27632 decreased contraction force, whereas combination of Y-27632 with either VDCC blockade or depletion of extracellular Ca2+ resulted in complete inhibition of [β-Ala⁸]-NKA(4-10)-induced contractions. In summary, our results indicate that the NK2Rs are linked exclusively to Gq/11-proteins in the UBSM and that the intracellular signaling involves the simultaneous activation of VDCC and the RhoA-ROCK pathway. These findings may help to identify potential therapeutic targets of bladder dysfunctions related to upregulation of TKs.

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S1049 Y-27632 2HCl Y-27632 2HCl is a selective ROCK1 (p160ROCK) inhibitor with Ki of 140 nM in a cell-free assay, exhibits >200-fold selectivity over other kinases, including PKC, cAMP-dependent protein kinase, MLCK and PAK. (592) (6)

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