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Block of inhibitory junction potentials and TREK-1 channels in murine colon by Ca2+ store-active drugs

By Sung Jin Hwang, Neil O/Kane, Cherie Singer, Sean M Ward, Kenton M Sanders and Sang Don Koh


Post-junctional enteric inhibitory responses are composed of at least two components attributed to the release of a purine and nitric oxide (NO). The nitrergic component is characterized by membrane potential hyperpolarization; however, the conductances involved and the role of Ca2+ stores in regulating these conductances are controversial. Conventional microelectrode recordings were performed in intact muscle strips and whole-cell voltage clamp experiments were performed on freshly dispersed cells and COS7 cells stably transfected with TREK-1 channels. Here we show that several Ca2+ store-active compounds, including caffeine, ryanodine, and cyclopiazonic acid, reduce inhibitory junction potentials and responses to sodium nitroprusside in murine colonic muscles. We previously proposed that two-pore K+ channels of the TREK family mediate a portion of the hyperpolarization response to NO in colonic muscles. We tested the effects of Ca2+ store-active drugs in COS cells expressing murine TREK-1 channels and found these compounds block TREK-1 currents. These effects were greatly attenuated by dialysing cells with protein kinase A inhibitory peptide (PKAI). Caffeine also blocked stretch-dependent K+ (SDK) channels, thought to be due to expression of TREK channels, in colonic myocytes, but these effects were not apparent in excised patches. Taken together our data show that Ca2+ store-active compounds inhibit TREK-1 channels, native SDK channels, and nitrergic inhibitory junction potentials. These effects appear to be due, in part, to the cAMP/PKA stimulatory actions of these drugs and inhibitory effects of TREK channels

Topics: Alimentary
Publisher: Blackwell Science Inc
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Provided by: PubMed Central
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