The Functional Study of Prostaglandin E₂ via EP Receptor on Pacemaker Activity in Interstitial Cells of Cajal from...

The interstitial cells of Cajal (ICC) generate spontaneous pacemaker activities responsible for producing slow waves in the gut smooth muscles. Prostaglandin E₂ (PGE₂) is one of the most important prostanoids in the gut, playing a crucial role in multiple physiological and pathological processes. Because information regarding the effects of PGE₂ on colonic ICC is limited, we investigated the effects of PGE₂ and its underlying signaling pathways in murine colonic ICC. Whole-cell patch-clamp recordings and reverse transcription polymerase chain reaction (RT-PCR) analyses were performed to evaluate the effects of PGE₂ on mouse colonic ICC. PGE₂ had a dual effect on pacemaker potential in the current-clamp mode. RT-PCR data suggested the expression of EP3 and EP4 receptors in colonic ICC. Low PGE₂ concentrations induced membrane depolarization and generation of pacemaker activities. And this effect is mimicked by sulprostone (an EP3 agonist). The low PGE₂ concentration-induced effect was inhibited by anoctamin-1 (ANO1) or a T-type Ca²⁺ channel blocker. Conversely, high PGE₂ concentrations induced membrane hyperpolarization and blocked pacemaker potential generation. However, this inhibitory effect was blocked by an ATP-sensitive potassium (K_ATP) channel blocker but not by other K⁺ channel blockers. Low concentrations of PGE₂ activated EP3 receptors, leading to excitation of pacemaker activity through regulation of ANO1 and T-type Ca²⁺ channels in colonic ICC. In contrast, higher concentrations of PGE₂ activated EP4 receptors and opened ATP-sensitive K⁺ channels, resulting in inhibition of pacemaker activity in colonic ICC.