Korean J Physiol Pharmacol.  2013 Apr;17(2):149-156. 10.4196/kjpp.2013.17.2.149.

Effects of Histamine on Cultured Interstitial Cells of Cajal in Murine Small Intestine

• Kim BJ
• Kwon YK
• Kim E
• So I

• KMID: 1429386
• DOI: http://doi.org/10.4196/kjpp.2013.17.2.149

Abstract

Interstitial cells of Cajal (ICCs) are the pacemaker cells in the gastrointestinal tract, and histamine is known to regulate neuronal activity, control vascular tone, alter endothelial permeability, and modulate gastric acid secretion. However, the action mechanisms of histamine in mouse small intestinal ICCs have not been previously investigated, and thus, in the present study, we investigated the effects of histamine on mouse small intestinal ICCs, and sought to identify the receptors involved. Enzymatic digestions were used to dissociate ICCs from small intestines, and the whole-cell patch-clamp configuration was used to record potentials (in current clamp mode) from cultured ICCs. Histamine was found to depolarize resting membrane potentials concentration dependently, and whereas 2-PEA (a selective H1 receptor agonist) induced membrane depolarizations, Dimaprit (a selective H2-agonist), R-alpha-methylhistamine (R-alpha-MeHa; a selective H3-agonist), and 4-methylhistamine (4-MH; a selective H4-agonist) did not. Pretreatment with Ca(2+)-free solution or thapsigargin (a Ca(2+)-ATPase inhibitor in endoplasmic reticulum) abolished the generation of pacemaker potentials and suppressed histamine-induced membrane depolarization. Furthermore, treatments with U-73122 (a phospholipase C inhibitor) or 5-fluoro-2-indolyl des-chlorohalopemide (FIPI; a phospholipase D inhibitor) blocked histamine-induced membrane depolarizations in ICCs. On the other hand, KT5720 (a protein kinase A inhibitor) did not block histamine-induced membrane depolarization. These results suggest that histamine modulates pacemaker potentials through H1 receptor-mediated pathways via external Ca2+ influx and Ca2+ release from internal stores in a PLC and PLD dependent manner.

Keyword

Gastrointestinal tract; Histamine; ICCs; Interstitial cells of cajal

MeSH Terms

Animals
Carbazoles
Cyclic AMP-Dependent Protein Kinases
Dimaprit
Domperidone
Estrenes
Gastric Acid
Gastrointestinal Tract
Hand
Histamine
Indoles
Interstitial Cells of Cajal
Intestine, Small
Membrane Potentials
Membranes
Methylhistamines
Mice
Neurons
Permeability
Phospholipase D
Pyridoxal
Pyrroles
Pyrrolidinones
Thapsigargin
Type C Phospholipases
Carbazoles
Cyclic AMP-Dependent Protein Kinases
Dimaprit
Domperidone
Estrenes
Histamine
Indoles
Methylhistamines
Phospholipase D
Pyridoxal
Pyrroles
Pyrrolidinones
Thapsigargin
Type C Phospholipases

Figure

• 

  Fig. 1 Effects of histamine on pacemaker potentials in cultured ICCs from murine small intestine. (A~C) show the pacemaker potentials of ICCs exposed to histamine (10~100µM) in current clamp mode (I=0). Responses to histamine are summarized in (D). Bars represent mean values±SEs. **: p<0.01. Significantly different from untreated controls. CTRL, control.

• 

  Fig. 2 Effects of histamine receptor subtype agonists and antagonists on histamine-induced pacemaker potential responses in cultured ICCs. (A) Pacemaker potentials of ICCs exposed to 2-PEA (50µM). (B~D) Pacemaker potentials of ICCs exposed to Dimaprit, R-alpha-MeHa, or 4-MH. (E) Pacemaker potentials of ICCs exposed to histamine in the presence of cetirizine (a H1 receptor antagonist). Responses to agonists or antagonists are summarized in (F). Bars represent mean values±SEs. **: p<0.01. Significantly different from untreated controls.

• 

  Fig. 3 Effects of an external Ca2+-free solution and of thapsigargin on histamine-induced pacemaker potential responses in cultured ICCs. (A) External Ca2+-free solution abolished the generation of pacemaker potentials, and blocked histamine-induced depolarizations. (B) Thapsigargin (5µM) abolished the generation of pacemaker potentials and also blocked histamine-induced depolarizations. Responses to histamine in external Ca2+-free solution and in the presence of thapsigargin are summarized in (C). Bars represent mean values±SEs. **: p<0.01. Significantly different from untreated controls. CTRL, control.

• 

  Fig. 4 Effects of PLC, PLD, and PKA inhibitors on histamine-induced pacemaker potential responses in cultured ICCs. (A) Pacemaker potentials of cultured ICCs exposed to histamine (50µM) in the presence of 5µM U-73122 (a PLC inhibitor). (B) Pacemaker potentials of cultured ICCs exposed to histamine in the presence of 1µM FIPI (a PLD inhibitor). (C) Pacemaker potentials of ICCs exposed to histamine in the presence of 1µM KT5720 (a PKA inhibitor). Responses to histamine in the presence of different inhibitors are summarized in (D). Bars represent mean values±SEs. **: p<0.01. Significantly different from untreated controls. CTRL, control.

• 

  Fig. 5 Effects of specific TRPC3 inhibitors on histamine-induced pacemaker potential responses in cultured ICCs. (A) Pacemaker potentials of cultured ICCs exposed to histamine (50µM) in the presence of 2µM pyr3 (a specific TRPC3 inhibitor). Responses to histamine in the presence of pyr3 are summarized in (B). Bars represent mean values±SEs. **: p<0.01. Significantly different from untreated controls. CTRL, control.

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