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Ca(2+) signals evoked by histamine H1 receptors are attenuated by activation of prostaglandin EP2 and EP4 receptors in human aortic smooth muscle cells.

ABSTRACT: Histamine and prostaglandin E2 (PGE2 ), directly and via their effects on other cells, regulate the behaviour of vascular smooth muscle (VSM), but their effects on human VSM are incompletely resolved.The effects of PGE2 on histamine-evoked changes in intracellular free Ca(2+) concentration ([Ca(2+) ]i ) and adenylyl cyclase activity were measured in populations of cultured human aortic smooth muscle cells (ASMCs). Selective ligands of histamine and EP receptors were used to identify the receptors that mediate the responses.Histamine, via H1 receptors, stimulates an increase in [Ca(2+) ]i that is entirely mediated by activation of inositol 1,4,5-trisphosphate receptors. Selective stimulation of EP2 or EP4 receptors attenuates histamine-evoked Ca(2+) signals, but the effects of PGE2 on both Ca(2+) signals and AC activity are largely mediated by EP2 receptors.Two important inflammatory mediators, histamine via H1 receptors and PGE2 acting largely via EP2 receptors, exert opposing effects on [Ca(2+) ]i in human ASMCs.

SUBMITTER: Pantazaka E

PROVIDER: S-EPMC3724117 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Ca(2+) signals evoked by histamine H1 receptors are attenuated by activation of prostaglandin EP2 and EP4 receptors in human aortic smooth muscle cells.

Pantazaka Evangelia E Taylor Emily J A EJ Bernard William G WG Taylor Colin W CW

British journal of pharmacology 20130801 7

<h4>Background and purpose</h4>Histamine and prostaglandin E2 (PGE2 ), directly and via their effects on other cells, regulate the behaviour of vascular smooth muscle (VSM), but their effects on human VSM are incompletely resolved.<h4>Experimental approach</h4>The effects of PGE2 on histamine-evoked changes in intracellular free Ca(2+) concentration ([Ca(2+) ]i ) and adenylyl cyclase activity were measured in populations of cultured human aortic smooth muscle cells (ASMCs). Selective ligands of ...[more]

PMID: 23638853

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Project description:While the role of prostaglandin E2 (PGE2) in promoting malignant progression is well established, how to optimally block the activity of PGE2 signaling remains to be demonstrated. Clinical trials with prostaglandin pathway targeted agents have shown activity but without sufficient significance or dose-limiting toxicities that have prevented approval. PGE2 signals through four receptors (EP1-4) to modulate tumor progression. EP2 and EP4 signaling exacerbates tumor pathology and is immunosuppressive through potentiating cAMP production. EP1 and EP3 signaling has the opposite effect through increasing IP3 and decreasing cAMP. Using available small-molecule antagonists of single EP receptors, the cyclooxygenase-2 (COX-2) inhibitor celecoxib, or a novel dual EP2/EP4 antagonist generated in this investigation, we tested which approach to block PGE2 signaling optimally restored immunologic activity in mouse and human immune cells and antitumor activity in syngeneic, spontaneous, and xenograft tumor models. We found that dual antagonism of EP2 and EP4 together significantly enhanced the activation of PGE2-suppressed mouse and human monocytes and CD8+ T cells in vitro as compared with single EP antagonists. CD8+ T-cell activation was dampened by single EP1 and EP3 antagonists. Dual EP2/EP4 PGE2 receptor antagonists increased tumor microenvironment lymphocyte infiltration and significantly reduced disease burden in multiple tumor models, including in the adenomatous polyposis coli (APC)min+/- spontaneous colorectal tumor model, compared with celecoxib. These results support a hypothesis that redundancy of EP2 and EP4 receptor signaling necessitates a therapeutic strategy of dual blockade of EP2 and EP4. Here we describe TPST-1495, a first-in-class orally available small-molecule dual EP2/EP4 antagonist.SignificanceProstaglandin (PGE2) drives tumor progression but the pathway has not been effectively drugged. We demonstrate significantly enhanced immunologic potency and antitumor activity through blockade of EP2 and EP4 PGE2 receptor signaling together with a single molecule.

Dataset Information

Ca(2+) signals evoked by histamine H1 receptors are attenuated by activation of prostaglandin EP2 and EP4 receptors in human aortic smooth muscle cells.

Publications

Ca(2+) signals evoked by histamine H1 receptors are attenuated by activation of prostaglandin EP2 and EP4 receptors in human aortic smooth muscle cells.

Similar Datasets

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