Journal Mobile Options
Table of Contents
Vol. 85, No. 4, 2012
Issue release date: June 2012
Digestion 2012;85:266–275

Role of Calcium in Activation of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels Caused by Cholecystokinin Octapeptide in Interstitial Cells of Cajal

Si X. · Huang L. · Gong Y. · Lu J. · Lin L.
aDepartment of Pediatric Surgery, Nanjing Children’s Hospital, and bDepartment of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


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 (Ca2+)-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 (Ih) 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 Ih. CCK-8S-facilitated Ih in cultured ICCs could be inhibited by CsCl and ZD7288. When cultured ICCs were exposed to Ca2+-free solution, no significant changes could be recorded by application of CCK-8S on Ih, 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.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Thomsen L, Robinson TL, Lee JCF, Farraway L, Hughes MJG, Andrews DW, Huizinga JD: Interstitial cells of Cajal generate a rhythmic pacemaker current. Nat Med 1998;4:848–851.
  2. Vanderwinden JM, Rumessen JJ: Interstitial cells of Cajal in human gut and gastrointestinal disease. Microsc Res Tech 1999;47:344–360.
  3. Sanders KM, Koh SD, Ordog T, Ward SM: Ionic conductances involved in generation and propagation of electrical slow waves in phasic gastrointestinal muscles. Neurogastroenterol Motil 2004;16(suppl 1):100–105.

    External Resources

  4. Sanders KM, Koh SD, Ward SM: Interstitial cells of Cajal as pacemakers in the gastrointestinal tract. Annu Rev Physiol 2006;68:307–343.
  5. Hashitani H: Interaction between interstitial cells and smooth muscles in the lower urinary tract and penis. J Physiol 2006;576:707–714.
  6. Lavoie B, Balemba OB, Nelson MT, Ward SM, Mawe GM: Morphological and physiological evidence for interstitial cell of Cajal-like cells in the guinea pig gallbladder. J Physiol 2007;579:487–501.
  7. Beckett EA, Ro S, Bayguinov Y, Sanders KM, Ward SM: Kit signaling is essential for development and maintenance of interstitial cells of Cajal and electrical rhythmicity in the embryonic gastrointestinal tract. Dev Dyn 2007;236:60–72.
  8. Beckett EA, McGeough CA, Sanders KM, Ward SM: Pacing of interstitial cells of Cajal in the murine gastric antrum: neurally mediated and direct stimulation. J Physiol 2003;553:545–559.
  9. MacIntosh CG, Andrews JM, Jones KL, Wishart JM, Morris HA, Jansen JB, Morley JE, Horowitz M, Chapman IM: Effects of age on concentrations of plasma cholecystokinin, glucagon-like peptide 1, and peptide YY and their relation to appetite and pyloric motility. Am J Clin Nutr 1999;69:999–1006.
  10. Wu T, Wang H-L: The excitatory effect of cholecystokinin on rat neostriatal neurons: ionic and molecular mechanisms. Eur J Pharmacol 1996;307:125–132.
  11. Varga G, Balint A, Burghardt B, Damato M: Involvement of endogenous CCK and CCK1 receptors in colonic motor function. Br J Pharmacol 2004;141:1275–1284.
  12. Yamazawa T, Iino M: Simultaneous imaging of Ca2+ signals in interstitial cells of Cajal and longitudinal smooth muscle cells during rhythmic activity in mouse ileum. J Physiol 2002;538:823–835.
  13. Ordog T, Ward SM, Sanders KM: Interstitial cells of cajal generate electrical slow waves in the murine stomach. J Physiol 1999;518:257–269.
  14. Aliakmal M, Herve C, Adrian M, Peter A: McNaughton. Role of the hyperpolarization-activated current Ih in somatosensory neurons. J Physiol 2008;586:5911–5929.

    External Resources

  15. Robinson RB, Siegelbaum SA: Hyperpolarization-activated cation currents: from molecules to physiological function. Annu Rev Physiol 2003;65:453–480.
  16. Dickens EJ, Hirst GD, Tomita T: Identification of rhythmically active cells in guinea-pig stomach. J Physiol 1999;514:515–531.
  17. Suzuki H, Ward SM, Bayguinov YR, Edwards FR, Hirst GD: Involvement of intramuscular interstitial cells in nitrergic inhibition in the mouse gastric antrum. J Physiol 2003;546:751–763.
  18. Yukari T, Sang DK, Kenton MS, Sean MW: Differential expression of ionic conductances in interstitial cells of Cajal in the murine gastric antrum. J Physiol 2008;586:859–873.

    External Resources

  19. Muinuddin A, Neshatian L, Gaisano HY, Diamant NE: Calcium source diversity in feline lower esophageal sphincter circular and sling muscle. Am J Physiol Gastrointest Liver Physiol 2004;286:G271–G277.
  20. Si XM, Huang L, Lv P, Xia H, Luo HS: Effects of cholecystokinin-8 induced gastric dysmotility on bile regurgitation during stress and molecular mechanisms. Regul Peptid 2006;136:64–71.
  21. Si XM, Huang L, Paul SC, An P, Luo HS: Signal transduction pathways mediating CCK-8S-induced gastric antral smooth muscle contraction. Digestion 2006;73:249–258.
  22. Sanders KM: A case for interstitial cells of Cajal as pacemakers and mediators of neurotransmission in the gastrointestinal tract. Gastroenterology 1996;111:492–515.
  23. Huang X, Xu WX: The pacemaker functions of visceral interstitial cells of Cajal. Sheng Li Xue Bao 2010;62:387–397.
  24. Robinson RB, Siegelbaum SA: Hyperpolarization-activated cation currents: from molecules to physiological function. Annu Rev Physiol 2003;65:453–480.
  25. DiFrancesco D: Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol 1993;55:455–472.
  26. Poolos NP, Migliore M, Johnston D: Pharmacological upregulation of h-channels reduces the excitability of pyramidal neuron dendrites. Nat Neurosci 2002;5:767–774.
  27. Meuth SG, Kanyshkova T, Meuth P, Landgraf P, Munsch T, Ludwig A, Hofmann F, Pape HC, Budde T: Membrane resting potential of thalamocortical relay neurons is shaped by the interaction among TASK3 and HCN2 channels. J Neurophysiol 2006;96:1517–1529.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50