Prostanoid EP3 receptor agonist sulprostone enhances pacemaker activity of colonic interstitial cells of Cajal

Abstract

EP receptor activation by PGE2 regulates gastrointestinal motility by modulating smooth muscle contractility. Interstitial cells of Cajal (ICCs) are pacemaker cells that regulate smooth muscle activity. We aimed to determine effects of the EP3 receptor agonist sulprostone on pacemaker potentials in colonic ICCs. We performed a whole cell patch clamp, RT-PCR, and Ca imaging in cultured ICCs from mouse colon. Sulprostone depolarized the membrane and increased pacemaker frequency. EP3 receptor antagonist blocked these sulprostone-induced effects. EP3 receptors were expressed in ANO1-positive ICCs. Phospholipase C inhibitor or Ca-ATPase inhibitor from the endoplasmic reticulum blocked the sulprostone-induced effects and sulprostone increased intracellular Ca ([Ca]) oscillations. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blockers also suppressed the sulprostone-induced effects. Sulprostone enhanced pacemaker activity through EP3 receptors by activating HCN channels via the [Ca] release pathway. Therefore, EP3 receptor activation in ICCs may modulate colonic motility and could be a therapeutic target for enhancing colonic GI motility.

Hyperpolarization‐activated cyclic nucleotide‐gated channels working as pacemaker channels in colonic interstitial cells of Cajal

“…However, sulprostone had no effects on pacemaker potentials in small intestinal ICC. 21 Thus, in this study, to confirm the functional data of sulprostone, we measured the maximum rate of rise of the resting membrane of pacemaker potentials of colonic ICC. Sulprostone increased the maximum rate of rise of the resting membrane of pacemaker potentials and decreased the duration and interval of pacemaker potentials.…”

“… 19 Sulprostone, a PGE 2 ‐EP 3 agonist, also enhanced the pacemaking potential frequency of colonic ICC, and the enhanced effects were blocked by HCN channel blockers. 21 Thus, we suggest that HCN channels are candidate pacemaker channels modulated by endogenous substances in colonic ICC. However, our previous results were mainly obtained using pharmacological studies.…”

“…Sulprostone, a prostaglandin E2‐EP3 receptor agonist, increased pacemaking potential frequency, which was blocked by HCN channel blockers in cultured colonic ICC, indicating that sulprostone activates HCN channels. 21 In cardiac sinoatrial cells, HCN channels were involved in diastolic depolarization of action potential. Thus, to determine whether diastolic depolarization of pacemaker potential in colonic ICC was affected by sulprostone, we evaluated the maximum increase in diastolic depolarization in cultured colonic ICC.…”

Acid increases PGE₂ in the duodenal mucosa in rats

“…Regarding the EP3 receptor, PGE 2 /EP3 is reported to be associated with the regulation of gastrointestinal motility. (15) Although its exact role is still unknown, it is interesting that EP3 receptors were abundantly seen at the intermuscular plexus. Together with the findings that COX-1 mRNA, COX-2 mRNA, and PG synthases mRNA were mainly observed in the deep duodenal mucosa, the role of prostaglandin for the regulation of visceromotor function might be largely dependent on the EP3 receptor.…”

“…On the other hand, we recently reported that the release of PGE 2 by activating TRPA1 channels promotes rectal colon contraction, (14) while the activation of EP3 receptors has been reported to regulate gastrointestinal motility. (15) These reports suggest association of PGE 2 with gastrointestinal motility.…”