Succinate, increased in metabolic syndrome, activates GPR91 receptor signaling in urothelial cells

Add time:09/02/2019    Source:sciencedirect.com

Metabolic syndrome is associated with overactive bladder syndrome (OAB) and increased circulating levels of succinate, an intermediate of the Krebs cycle. The urothelium is an essential regulator of bladder muscle contraction. This study aimed to determine if GPR91, the succinate receptor, is expressed and functional in the bladder. Urothelial and smooth muscle cells (SMCs) were cultured and characterized. PCR revealed that urothelial cells express GPR91, twice as much as SMCs. Incubation of cells with succinate stimulated phosphorylation of ERK and JNK in urothelial cells. Succinate also potently inhibited forskolin-stimulated cyclic AMP production in urothelial cells, an effect prevented by a protein Gi inhibitor. ERK phosphorylation stimulated by succinate was abolished by inhibitors of protein Gq, phospholipase C, MAPK pathway and PKC. Incubation of urothelial cells with succinate potently increased iNOS synthesis and secretion of nitric oxide (NO), and decreased secretion of prostaglandin E2 (PGE2). Finally, succinate triggered entry of calcium in urothelial cells. GPR91 knockdown by shRNA abolished most of these signaling effects. We conclude that in the bladder, urothelial cells are a primary target of succinate through its receptor GPR91. Its activation leads to signaling via phospholipase C, MAPK, PKC pathway and protein Gq and Gi. Succinate binding to GPR91 triggers a rise in intracellular calcium, an increase in secretion of NO and a decrease in the release of PGE2. Succinate might be essential in the understanding of OAB that occurs in metabolic syndrome.

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