Involvement of transient receptor potential melastatin type 7 channels on Poncirus fructus-induced depolarizations of pacemaking activity in interstitial cells of Cajal from murine small intestine

다국어 초록 (Multilingual Abstract)

Background: Extracts of Poncirus trifoliata (L.) Raf. (Rutaceae; PT) are widely used as a traditional medicine in Eastern Asia, especially for the treatment of gastrointestinal (GI) disorders related to GI motility. Interstitial cells of Cajal (ICCs) are pacemakers in the GI tract, and transient receptor potential melastatin type 7 (TRPM7) channels and Ca2+ activated Cl– channels are candidate pacemaker channels.
Methods: In the present study, the effects of a methanolic extract of the dried roots of PT on ICC pacemaking activity were examined using the whole-cell patch-clamp technique.
Results: The methanolic extract of PT (PTE) was found to decrease the amplitudes of pacemaker potentials in ICC clusters and to depolarize the resting membrane potentials in a concentration-dependent manner. Intracellular GDP-β-S suppressed PTE-induced depolarizations, and pretreatment with a U-73122 (a phospholipase C inhibitor) or with 2-APB (an 1,4,5-inositol triphosphate receptor inhibitor) abolished this generation of pacemaker potentials and suppressed PTE-induced effects. The applications of flufenamic acid, niflumic acid, waixenicin A, or 5-lipoxygenase inhibitors (NDGA or AA861) abolished this generation of pacemaker potentials and inhibited PTE-induced membrane depolarization. Furthermore, PTE inhibited TRPM7 channels but did not affect Ca2+-activated Cl– channels (both channels play important roles in the modulation of the pacemaking activity related to GI motility).
Conclusion: These results suggest that the PTE-induced depolarization of pacemaking activity occurs in a G-protein-, phospholipase C-, and 1,4,5-inositol triphosphate-dependent manner via TRPM7 channels in cultured ICCs from murine small intestine, which indicates that ICCs are PTE targets and that their interactions affect intestinal motility.

참고문헌 (Reference)

1 Zierler S, "Waixenicin A. inhibits cell proliferation through magnesium-dependent block of transient receptor potential melastatin 7 (TRPM7) channels" 286 : 39328-39335, 2011

2 Huizinga JD, "W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity" 373 : 347-349, 1995

3 Brauchi S, "TRPM7facilitates cholinergic vesicle fusion with the plasma membrane" 105 : 8304-8308, 2008

4 Sahni J, "TRPM7 ion channels are required for sustained phosphoinositide 3-kinase signaling in lymphocytes" 8 : 84-93, 2008

5 Yang YD, "TMEM16A confers receptor-activated calcium-dependent chloride conductance" 455 : 1210-1215, 2008

6 Kim BJ, "Suppression of transient receptor potential melastatin 7 channel induces cell death in gastric cancer" 99 : 2502-2509, 2008

7 Koh SD, "Spontaneous electrical rhythmicity in cultured interstitial cells of Cajal from the murine small intestine" 513 : 203-213, 1998

8 Yoo HY, "Role of thromboxane A2-activated nonselective cation channels in hypoxic pulmonary vasoconstriction of rat" 302 : C307-C317, 2012

9 Schmitz C, "Regulation of vertebrate cellular Mg2+homeostasis by TRPM7" 114 : 191-200, 2003

10 Lee HT, "Prokinetic activity of an aqueous extract from dried immature fruit of Poncirus trifoliata (L.) Raf" 102 : 131-136, 2005

11 Yi JM, "Poncirus trifoliata fruit induces apoptosis in human promyelocytic leukemia cells" 340 : 179-185, 2004

12 Kim BJ, "Melastatin-type transient receptor potential channel 7 is required for intestinal pacemaking activity" 129 : 1504-1517, 2005

13 Vriens J, "Invertebrate TRP proteins as functional models for mammalian channels" 449 : 213-226, 2004

14 Abed E, "Importance of melastatin-like transient receptor potential 7 and magnesium in the stimulation of osteoblast proliferation and migration by platelet derived growth factor" 297 : C360-C368, 2009

15 Huizinga JD, "High-conductance chloride channels generate pacemaker currents in interstitial cells of Cajal" 123 : 1627-1636, 2002

16 Choi KH, "Hexane extract of Poncirus trifoliata (L.) Raf. stimulates the motility of rat distal colon" 127 : 718-724, 2010

17 Hwang SJ, "Expression of anoctamin 1/TMEM16A by interstitial cells of Cajal is fundamental for slow wave activity in gastrointestinal muscles" 587 : 4887-4904, 2009

18 Guilbert A, "Evidence that TRPM7 is required for breast cancer cell proliferation" 297 : C493-C502, 2009

19 김병주, "Effects of Transient Receptor Potential Channel Blockers on Pacemaker Activity in Interstitial Cells of Cajal from Mouse Small Intestine" 한국분자세포생물학회 32 (32): 153-160, 2011

20 Lee HT, "Effect of an aqueous extract of dried immature fruit of Poncirus trifoliata (L.) Raf. on intestinal transit in rodents with experimental gastrointestinal motility dysfunctions" 102 : 302-306, 2005

21 Sanders KM, "Development and plasticity of interstitial cells of Cajal" 11 : 311-338, 1999

22 Elizondo MR, "Defective skeletogenesis with kidney stone formation in dwarf zebrafish mutant for trpm7" 15 : 667-671, 2005

23 Chen HC, "Blockade of TRPM7 channel activity and cell death by inhibitors of 5-lipoxygenase" 5 : e11161-, 2010

24 Kim DH, "Anti-Helicobacter pylori activity of the metabolites of poncirin from Poncirus trifoliata by human intestinal bacteria" 22 : 422-424, 1999

25 Mazzone A, "Altered expression of ano1 variants in human diabetic gastroparesis" 286 : 13393-13403, 2011

26 Aarts M, "A key role for TRPM7 channels in anoxic neuronal death" 115 : 863-877, 2003

27 Sanders KM, "A case for interstitial cells of Cajal as pacemakers and mediators of neurotransmission in the gastrointestinal tract" 111 : 492-515, 1996

28 Koh SD, "A Ca2+-inhibited nonselective cation conductance contributes to pacemaker currents in mouse interstitial cell of Cajal" 540 : 803-814, 2002

29 Zhu MH, "A Ca2+-activated Cl–conductance in interstitial cells of Cajal linked to slow wave currents and pacemaker activity" 587 : 4905-4918, 2009