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

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Abstract
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 Ca2+concentration, and RhoA activity were measured in the 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 the intracellular Ca2+concentration increase were abolished. Although Gq/11proteins are linked principally to phospholipase Cβ and inositol trisphosphate-mediated Ca2+release from intracellular stores, we found that phospholipase Cβ 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 (VDCCs) 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 with Y-27632 decreased contraction force, whereas the 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 NK2Rs are linked exclusively to Gq/11proteins 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.
Funding Information
  • OTKA (H07-B-74286, K-112964, K-125174)
  • NVKP (NVKP_16-1-2016-0042)
  • Ministry of Human Capacities, Hungary (EFOP-3.6.3-VEKOP-16-2017-00009)

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