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Hydrogen Sulfide as an Allosteric Modulator of ATP-Sensitive Potassium Channels in Colonic Inflammation

Molecular Pharmacology, ISSN: 0026-895X, Vol: 83, Issue: 1, Page: 294-306
2013
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The ATP-sensitive potassium channel (K ATP ) in mouse colonic smooth muscle cell is a complex containing a pore-forming subunit (Kir6.1) and a sulfonylurea receptor subunit (SUR2B). These channels contribute to the cellular excitability of smooth muscle cells and hence regulate the motility patterns in the colon. Whole-cell voltage-clamp techniques were used to study the alterations in K ATP channels in smooth muscle cells in experimental colitis. Colonic inflammation was induced in BALB/C mice after intracolonic administration of trinitrobenzene sulfonic acid. K ATP currents were measured at a holding potential of −60 mV in high K + external solution. The concentration response to levcromakalim (LEVC), a K ATP channel opener, was significantly shifted to the left in the inflamed smooth-muscle cells. Both the potency and maximal currents induced by LEVC were enhanced in inflammation. The EC 50 values in control were 6259 nM ( n = 10) and 422 nM ( n = 8) in inflamed colon, and the maximal currents were 9.9 ± 0.71 pA/pF (60 μ M) in control and 39.7 ± 8.8 pA/pF (3 μ M) after inflammation. As was seen with LEVC, the potency and efficacy of sodium hydrogen sulfide (NaHS) (10–1000 μ M) on K ATP currents were significantly greater in inflamed colon compared with controls. In control cells, pretreatment with 100 µ M NaHS shifted the EC 50 for LEV-induced currents from 2838 ( n = 6) to 154 ( n = 8) nM. Sulfhydration of sulfonylurea receptor 2B (SUR2B) was induced by NaHS and colonic inflammation. These data suggest that sulfhydration of SUR2B induces allosteric modulation of K ATP currents in colonic inflammation.

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