Receptor GPR91 contributes to voiding function and detrusor relaxation mediated by succinate.
ATP
GPR91 KO mice
bladder contractility
cystometry
nitric oxide
organ bath
Journal
Neurourology and urodynamics
ISSN: 1520-6777
Titre abrégé: Neurourol Urodyn
Pays: United States
ID NLM: 8303326
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
27
07
2020
revised:
16
09
2020
accepted:
13
10
2020
pubmed:
25
10
2020
medline:
12
6
2021
entrez:
24
10
2020
Statut:
ppublish
Résumé
Succinate activates the receptor GPR91 identified in the bladder. The present study aims to unravel the mechanisms of bladder relaxation by succinate and how the receptor is involved in structural and functional changes of the bladder. Physiological recordings of bladder function were carried out by cystometry and organ bath from C57BL/6 mice, homozygous GPR91 Bladders of GPR91 KO mice had a greater mass to body weight ratio with a thicker bladder wall compared to C57BL/6 mice. They also displayed increased basal and maximal bladder pressures, and decreased intercontraction intervals, bladder capacity, micturition volume, and compliance. During cystometry, bladders of SD rats and C57BL/6 mice instilled with succinate (10 mM) showed signs of relaxation while bladders of GPR91 KO mice were unresponsive. Similarly, in organ bath, succinate relaxed bladder strips preincubated with carbachol, except GPR91 KO ones. Relaxation was stronger in the presence of urothelium and independent of NO synthesis. Bladder strips from all mice groups showed similar responses to KCl, carbachol, and electrical stimulation. In vitro, succinate increased NO secretion in urothelial cell culture of both C57BL6 and GPR91 KO mice while ATP secretion was potently decreased by succinate in C57BL6 culture only. Succinate through GPR91 is essential to bladder structure and contraction. GPR91 relaxes the detrusor partially by decreasing urothelial ATP secretion.
Substances chimiques
GPR91 protein, mouse
0
Receptors, G-Protein-Coupled
0
Succinic Acid
AB6MNQ6J6L
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
120-130Informations de copyright
© 2020 Wiley Periodicals LLC.
Références
Ariza AC, Deen PM, Robben JH. The succinate receptor as a novel therapeutic target for oxidative and metabolic stress-related conditions. Front Endocrinol. 2012;3:22.
Krebs HA. Rate control of the tricarboxylic acid cycle. Adv Enzyme Regul. 1970;8:335-353.
Sapieha P, Sirinyan M, Hamel D, et al. The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis. Nature Med. 2008;14(10):1067-1076.
Toma I, Kang JJ, Sipos A, et al. Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney. J Clin Investig. 2008;118(7):2526-2534.
He W, Miao FJ-P, Lin DC-H, et al. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature. 2004;429(6988):188-193.
Davili Z, Johar S, Hughes C, Kveselis D, Hoo J. Succinate dehydrogenase deficiency associated with dilated cardiomyopathy and ventricular noncompaction. Eur J Pediatr. 2007;166(8):867-870.
Pajor A. Molecular properties of sodium/dicarboxylate cotransporters. J Membr Biol. 2000;175(1):1-8.
Gilissen J, Jouret F, Pirotte B, Hanson JJP. Insight into SUCNR1 (GPR91) structure and function. Pharmacol Ther. 2016;159:56-65.
Mossa A, Velasquez Flores M, Nguyen H, Cammisotto PG, Campeau L. Beta-3 adrenoceptor signaling pathways in urothelial and smooth muscle cells in the presence of succinate. J Pharmacol Exp Ther. 2018;367(2):252-259.
Mossa AH, Velasquez Flores M, Cammisotto PG, Campeau L. Succinate, increased in metabolic syndrome, activates GPR91 receptor signaling in urothelial cells. Cell Signal. 2017;37:31-39.
Mills E, O'Neill L. Succinate: a metabolic signal in inflammation. Trends Cell Biol. 2013;20:1-8.
Velasquez Flores M, Mossa AH, Cammisotto P, Campeau L. Succinate decreases bladder function in a rat model associated with metabolic syndrome. Neurourol Urodyn. 2018;37(5):1549-1558.
Murphy MP, O'Neill LA. Krebs cycle reimagined: the emerging roles of succinate and itaconate as signal transducers. Cell. 2018;174(4):780-784.
Grisham MB, Johnson GG, Lancaster JR. Quantitation of nitrate and nitrite in extracellular fluids. Methods Enzymol. 1996;268(A):237-246.
Rubic T, Lametschwandtner G, Jost S, et al. Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nature Immunol. 2008;9(11):1261-1269.
Burnstock G. Purinergic signalling in the urinary tract in health and disease. Purinergic Signal. 2014;10(1):103-155.
Leite LN, Gonzaga NA, Simplicio JA, et al. Pharmacological characterization of the mechanisms underlying the vascular effects of succinate. Eur J Pharmacol. 2016;789:334-343.
Palmer RM, Ferrige A, Moncada SJN. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327(6122):524-526.
Birder LA, Nealen ML, Kiss S, et al. β-Adrenoceptor agonists stimulate endothelial nitric oxide synthase in rat urinary bladder urothelial cells. J Neurosci. 2002;22(18):8063-8070.
Satake Y, Satoh K, Nogi M, et al. Crucial roles of nitric oxide synthases in β-adrenoceptor-mediated bladder relaxation in mice. Am J Physiol Renal Physiol. 2016;312(1):F33-F42.
Matsumoto-Miyai K, Yamada E, Yoshizumi M, Kawatani M. The regulation of distention-induced ATP release from urothelium by the adenylyl cyclase-cyclic AMP pathway. Biomed Res. 2012;33(3):153-157.
Kullmann FA, Daugherty SL, de Groat WC, Birder LA. Bladder smooth muscle strip contractility as a method to evaluate lower urinary tract pharmacology. J Vis Exp. 2014;(90):e51807.
Abrams P. Describing bladder storage function: overactive bladder syndrome and detrusor overactivity. Urology. 2003;62(5):28-37.
McCreath KJ, Espada S, Gálvez BG, et al. Targeted disruption of the SUCNR1 metabolic receptor leads to dichotomous effects on obesity. Diabetes. 2015;64(4):1154-1167.
Grimolizzi F, Arranz L. Multiple faces of succinate beyond metabolism in blood. Haematologica. 2018;103(10):1586-1592.