Abstract
Background: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate pacemaker activity in some cardiac cells and neurons. Little is known about the effects of cholecystokinin octapeptide (CCK-8) on HCN channels and excitability of murine interstitial cells of Cajal (ICCs). Methods: In the present study, the effects and mechanisms of CCK-8 on HCN channels were investigated by measuring mechanical contraction of smooth muscle strips and ionic channels of ICCs in murine gastric antrum. Results: Sulfated CCK-8 (CCK-8S) was used, and we found that CCK-8S increased the contraction of smooth muscle strips in the gastric antrum, which could be suppressed by specific HCN channel blockers CsCl and ZD7288. Extracellular calcium could also intensify the contraction. Under the same conditions, when antral strips were exposed to calcium ion (Ca<sup>2+</sup>)-free solution, no significant changes could be recorded with CCK-8S or ZD7288. Isolated ICCs from the murine gastric antrum identified by specific c-Kit antibody primers were chosen for electrophysiological recordings. HCN current (I<sub>h</sub>) of cultured ICCs was studied by whole-cell patch clamp techniques. A spontaneous transient inward current was recorded in ICCs, which could be inhibited by addition of CsCl and ZD7288; the current proved to be I<sub>h</sub>. CCK-8S-facilitated I<sub>h</sub> in cultured ICCs could be inhibited by CsCl and ZD7288. When cultured ICCs were exposed to Ca<sup>2+</sup>-free solution, no significant changes could be recorded by application of CCK-8S on I<sub>h</sub>, which proved extracellular calcium might have an excitatory effect on HCN channels. Conclusion: We demonstrate that HCN channels are present in ICCs in the murine gastric antrum; they might be an important regulator of ICC excitability and pacemaker activity and are strongly affected by CCK-8S. Extracellular calcium might be a trigger in the activation of HCN channels caused by CCK-8S in cultured ICCs.
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