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Tachykinins (TKs) are involved in both the physiological regulation of urinary bladder functions and development of overactive bladder 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 Ca 2+ concentration, and RhoA activity were measured in the mouse urinary bladder smooth muscle (UBSM). TKs and the NK2 receptor (NK2R)-specific agonist [β-Ala 8 ]-NKA(4–10) evoked contraction, which was inhibited by the NKR2 antagonist MEN10376. In Gα q/11 -deficient mice, [β-Ala 8 ]-NKA(4–10)-induced contraction and the intracellular Ca 2+ concentration increase were abolished. Although G q/11 proteins are linked principally to phospholipase Cβ and inositol trisphosphate-mediated Ca 2+ release from intracellular stores, we found that phospholipase Cβ inhibition and sarcoplasmic reticulum Ca 2+ depletion failed to have any effect on contraction induced by [β-Ala 8 ]-NKA(4–10). In contrast, lack of extracellular Ca 2+ or blockade of voltage-dependent Ca 2+ channels (VDCCs) suppressed contraction. Furthermore, [β-Ala 8 ]-NKA(4–10) increased RhoA activity in the UBSM in a G q/11 -dependent manner and inhibition of Rho kinase with Y-27632 decreased contraction force, whereas the combination of Y-27632 with either VDCC blockade or depletion of extracellular Ca 2+ resulted in complete inhibition of [β-Ala 8 ]-NKA(4–10)-induced contractions. In summary, our results indicate that NK2Rs are linked exclusively to G q/11 proteins in the UBSM and that the intracellular signaling involves the simultaneous activation of VDCC and the RhoA-Rho kinase pathway. These findings may help to identify potential therapeutic targets of bladder dysfunctions related to upregulation of TKs.

american journal of physiology. renal physiology./american journal of physiology. renal physiology

NK2 receptor-mediated detrusor muscle contraction involves G<sub>q/11</sub>-dependent activation of voltage-dependent Ca<sup>2+</sup>channels and the RhoA-Rho kinase pathway

NK2 receptor-mediated detrusor muscle contraction involves Gq/11-dependent activation of voltage-dependent Ca2+channels and the RhoA-Rho kinase pathway

NK2 receptor-mediated detrusor muscle contraction involves G_q/11-dependent activation of voltage-dependent Ca²⁺channels and the RhoA-Rho kinase pathway