title: Urothelium muscarinic activation phosphorylates CBS(Ser227) via cGMP/PKG pathway causing human bladder relaxation through H2S production.
abstract: The urothelium modulates detrusor activity through releasing factors whose nature has not been clearly defined. Here we have investigated the involvement of H2S as possible mediator released downstream following muscarinic (M) activation, by using human bladder and urothelial T24 cell line. Carbachol stimulation enhances H2S production and in turn cGMP in human urothelium or in T24 cells. This effect is reversed by cysthationine-β-synthase (CBS) inhibition. The blockade of M1 and M3 receptors reverses the increase in H2S production in human urothelium. In T24 cells, the blockade of M1 receptor significantly reduces carbachol-induced H2S production. In the functional studies, the urothelium removal from human bladder strips leads to an increase in carbachol-induced contraction that is mimicked by CBS inhibition. Instead, the CSE blockade does not significantly affect carbachol-induced contraction. The increase in H2S production and in turn of cGMP is driven by CBS-cGMP/PKG-dependent phosphorylation at Ser(227) following carbachol stimulation. The finding of the presence of this crosstalk between the cGMP/PKG and H2S pathway downstream to the M1/M3 receptor in the human urothelium further implies a key role for H2S in bladder physiopathology. Thus, the modulation of the H2S pathway can represent a feasible therapeutic target to develop drugs for bladder disorders.
authors: Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy.|Interdepartmental Centre for Sexual Medicine, University of Naples, Federico II, Via Sergio Pansini 5, Naples, 80131, Italy.
authors: Roberta
authors: R
authors: d'Emmanuele di Villa Bianca
authors: Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy.
authors: Emma
authors: E
authors: Mitidieri
authors: Interdepartmental Centre for Sexual Medicine, University of Naples, Federico II, Via Sergio Pansini 5, Naples, 80131, Italy.|Department of Neurosciences, Human Reproduction and Odontostomatology, University of Naples, Federico II, Naples, 80131, Italy.
authors: Ferdinando
authors: F
authors: Fusco
authors: Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy.
authors: Annapina
authors: A
authors: Russo
authors: Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy.
authors: Valentina
authors: V
authors: Pagliara
authors: Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy.
authors: Teresa
authors: T
authors: Tramontano
authors: Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy.
authors: Erminia
authors: E
authors: Donnarumma
authors: Interdepartmental Centre for Sexual Medicine, University of Naples, Federico II, Via Sergio Pansini 5, Naples, 80131, Italy.|Department of Neurosciences, Human Reproduction and Odontostomatology, University of Naples, Federico II, Naples, 80131, Italy.
authors: Vincenzo
authors: V
authors: Mirone
authors: Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy.|Interdepartmental Centre for Sexual Medicine, University of Naples, Federico II, Via Sergio Pansini 5, Naples, 80131, Italy.
authors: Giuseppe
authors: G
authors: Cirino
authors: Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy.
authors: Giulia
authors: G
authors: Russo
authors: Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy.|Interdepartmental Centre for Sexual Medicine, University of Naples, Federico II, Via Sergio Pansini 5, Naples, 80131, Italy.
authors: Raffaella
authors: R
authors: Sorrentino
mesh_terms: D002217:Carbachol / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D003541:Cystathionine beta-Synthase / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D010766:Phosphorylation; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D019459:Urothelium / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
chemical_list: D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D012694:Serine; D002217:Carbachol; D017869:Cyclic GMP-Dependent Protein Kinases; D003541:Cystathionine beta-Synthase; D006152:Cyclic GMP; D006862:Hydrogen Sulfide