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Pawan Kumar Shahi,임동윤,Dong Chaun Zuo,최석,Mi Jung Lee,정현숙,전제열 한국생약학회 2013 Natural Product Sciences Vol.19 No.4
In preliminary tests, we examined the effect of several fractions isolated from fermented pine needle extract on pacemaker potentials in cultured interstitial cells of Cajal (ICCs) from the mouse colon using a whole cell patch clamp technique. Among these fractions, Fraction 3 (F3) elicited the most powerful depolarization of membrane. Therefore, the aim of the present study was to investigate the effect of F3 obtained from fermented extract of Pinus densiflora needle on pacemaker potentials in ICCs and to establish its mechanism of action. Colonic ICCs generated spontaneous periodic pacemaker potentials in the current-clamp mode. F3 depolarized the membrane and decreased the frequency and amplitude of pacemaker potentials in a dose-dependent fashion. The F3-induced effects on pacemaker potentials were blocked by methoctramine, a muscarinic M2 receptor antagonist, and by glycopyrrolate, a muscarinic M3 receptor antagonist. The F3-induced effects on pacemaker potentials were blocked by external Na+-free solution and by flufenamic acid, a non-selective cation channel blocker, as well as by the removal of external Ca2+ and in the presence of thapsigargin, a Ca2+-ATPase inhibitor in the endoplasmic reticulum. Taken together, these results suggest that F3 of pine needle extract modulates the pacemaker activity of colonic ICCs by the activation of non-selective cation channels via muscarinic M2 and M3 receptors. And external Ca2+ influx and intracellular Ca2+ release are involved in F3 actions on ICCs.
Shahi, Pawan Kumar,Choi, Seok,Zuo, Dong Chuan,Kim, Man Yoo,Park, Chan Guk,Kim, Young Dae,Lee, Jun,Park, Kyu Joo,So, Insuk,Jun, Jae Yeoul Springer Japan 2014 Journal of gastroenterology Vol.49 No.6
<P><B>Background</B></P><P>Hyperpolarization-activated cyclic nucleotide (HCN) channels are pacemaker channels that regulate heart rate and neuronal rhythm in spontaneously active cardiac and neuronal cells. Interstitial cells of Cajal (ICCs) are also spontaneously active pacemaker cells in the gastrointestinal tract. Here, we investigated the existence of HCN channel and its role on pacemaker activity in colonic ICCs.</P><P><B>Methods</B></P><P>We performed whole-cell patch clamp, RT-PCR, and Ca<SUP>2+</SUP>-imaging in cultured ICCs from mouse mid colon.</P><P><B>Results</B></P><P>SQ-22536 and dideoxyadenosine (adenylate cyclase inhibitors) decreased the frequency of pacemaker potentials, whereas both rolipram (cAMP-specific phosphodiesterase inhibitor) and cell-permeable 8-bromo-cAMP increased the frequency of pacemaker potentials. CsCl, ZD7288, zatebradine, clonidine (HCN channel blockers), and genistein (a tyrosine kinase inhibitor) suppressed the pacemaker activity. RT-PCR revealed expression of HCN1 and HCN3 channels in c-kit and Ano1 positive colonic ICCs. In recordings of spontaneous intracellular Ca<SUP>2+</SUP> [Ca<SUP>2+</SUP>]<SUB>i</SUB> oscillations, rolipram and 8-bromo-cAMP increased [Ca<SUP>2+</SUP>]<SUB>i</SUB> oscillations, whereas SQ-22536, CsCl, ZD7288, and genistein decreased [Ca<SUP>2+</SUP>]<SUB>i</SUB> oscillations.</P><P><B>Conclusions</B></P><P>HCN channels in colonic ICCs are tonically activated by basal cAMP production and participate in regulation of pacemaking activity.</P>
Shahi, Pawan Kumar,Choi, Seok,Zuo, Dong Chuan,Yeum, Cheol-Ho,Yoon, Pyung-Jin,Lee, Jun,Kim, Young-Dae,Park, Chan-Guk,Kim, Man-Yoo,Shin, Hye-Rang,Oh, Hyun-Jung,Jun, Jae-Yeoul The Korean Society of Pharmacology 2011 The Korean Journal of Physiology & Pharmacology Vol.15 No.3
In this study we determined whether or not 5-hydroxytryptamine (5-HT) has an effect on the pacemaker activities of interstitial cells of Cajal (ICC) from the mouse small intestine. The actions of 5-HT on pacemaker activities were investigated using a whole-cell patch-clamp technique, intracellular $Ca^{2+}$ ($[Ca^{2+}]_i$) analysis, and RT-PCR in ICC. Exogenously-treated 5-HT showed tonic inward currents on pacemaker currents in ICC under the voltage-clamp mode in a dose-dependent manner. Based on RT-PCR results, we found the existence of 5-$HT_{2B,\;3,\;4,\;and\;7}$ receptors in ICC. However, SDZ 205557 (a 5-$HT_4$ receptor antagonist), SB 269970 (a 5-$HT_7$ receptor antagonist), 3-tropanylindole - 3 - carboxylate methiodide (3-TCM; a 5-$HT_3$ antagonist) blocked the 5-HT-induced action on pacemaker activity, but not SB 204741 (a 5-$HT_{2B}$ receptor antagonist). Based on $[Ca^{2+}]_i$ analysis, we found that 5-HT increased the intensity of $[Ca^{2+}]_i$. The treatment of PD 98059 or JNK II inhibitor blocked the 5-HT-induced action on pacemaker activity of ICC, but not SB 203580. In summary, these results suggest that 5-HT can modulate pacemaker activity through 5-$HT_{3,\;4,\;and\;7}$ receptors via $[Ca^{2+}]_i$ mobilization and regulation of mitogen-activated protein kinases.
Pawan Kumar Shahi,최석,Dong Chuan Zuo,염철호,윤평진,이준,김영대,박찬국,김만우,신혜랑,오현정,전제열 대한약리학회 2011 The Korean Journal of Physiology & Pharmacology Vol.15 No.3
In this study we determined whether or not 5-hydroxytryptamine (5-HT) has an effect on the pacemaker activities of interstitial cells of Cajal (ICC) from the mouse small intestine. The actions of 5-HT on pacemaker activities were investigated using a whole-cell patch-clamp technique, intracellular Ca^(2+) ([Ca^(2+)]i) analysis, and RT-PCR in ICC. Exogenously-treated 5-HT showed tonic inward currents on pacemaker currents in ICC under the voltage-clamp mode in a dose-dependent manner. Based on RT-PCR results, we found the existence of 5-HT2B, 3, 4, and 7 receptors in ICC. However, SDZ 205557 (a 5-HT4 receptor antagonist), SB 269970 (a 5-HT7 receptor antagonist), 3-tropanylindole − 3 − carboxylate methiodide (3-TCM; a 5-HT3 antagonist) blocked the 5-HT-induced action on pacemaker activity, but not SB 204741 (a 5-HT2B receptor antagonist). Based on [Ca^(2+)]i analysis, we found that 5-HT increased the intensity of [Ca^(2+)]i. The treatment of PD 98059 or JNK II inhibitor blocked the 5-HT-induced action on pacemaker activity of ICC, but not SB 203580. In summary, these results suggest that 5-HT can modulate pacemaker activity through 5-HT3, 4, and 7 receptors via [Ca^(2+)]i mobilization and regulation of mitogen-activated protein kinases.
Shahi, Pawan Kumar,Choi, Seok,Jeong, Yu Jin,Park, Chan Guk,So, Insuk,Jun, Jae Yeoul Springer-Verlag 2014 Naunyn-Schmiedeberg's archives of pharmacology Vol.387 No.7
<P>Cyclic guanosine 3',5'-monophosphate (cGMP) inhibited the generation of pacemaker activity in interstitial cells of Cajal (ICCs) from the small intestine. However, cGMP role on pacemaker activity in colonic ICCs has not been reported yet. Thus, we investigated the role of cGMP in pacemaker activity regulation by colonic ICCs. We performed a whole-cell patch-clamp and Ca(2+) imaging in cultured ICCs from mouse colon. 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, an inhibitor of guanylate cyclase) increased the pacemaker potential frequency, whereas zaprinast (an inhibitor of phosphodiesterase) and cell-permeable 8-bromo-cGMP decreased the pacemaker potential frequency. KT-5823 (an inhibitor of protein kinase G [PKG]) did not affect the pacemaker potential. L-N(G)-nitroarginine methyl ester (L-NAME, an inhibitor of nitric oxide [NO] synthase) increased the pacemaker potential frequency, whereas ()-S-nitroso-N-acetylpenicillamine (SNAP, a NO donor) decreased the pacemaker potential frequency. Glibenclamide (an ATP-sensitive K(+) channel blocker) did not block the effects of cell-permeable 8-bromo-cGMP and SNAP. Recordings of spontaneous intracellular Ca(2+) ([Ca(2+)]i) oscillations revealed that ODQ and L-NAME increased [Ca(2+)]i oscillations. In contrast, zaprinast, 8-bromo cGMP, and SNAP decreased the [Ca(2+)]i oscillations. Basal cGMP levels regulate the resting pacemaker potential frequency by the alteration on Ca(2+) release via a PKG-independent pathway. Additionally, the endogenous release of NO seems to be responsible maintaining basal cGMP levels in colonic ICCs.</P>
김영대,전제열,한경택,이준,박찬국,김만우,Pawan Kumar Shahi,Dong Chuan Zuo,최석 한국분자세포생물학회 2013 Molecules and cells Vol.35 No.1
Interstitial cells of Cajal (ICC) are the pacemaker cells that generate the rhythmic oscillation responsible for the production of slow waves in gastrointestinal smooth muscle. Spingolipids are known to present in digestive system and are responsible for multiple important physiological and pathological processes. In this study, we are interested in the action of sphingosine 1-phosphate (S1P) on ICC. S1P depolarized the membrane and increased tonic inward pacemaker currents. FTY720 phosphate (FTY720P, an S1P1,3,4,5 agonist) and SEW 2871 (an S1P1 agonist) had no effects on pacemaker activity. Suramin (an S1P3 antagonist) did not block the S1P-induced action on pacemaker currents. However, JTE-013 (an S1P2 antagonist) blocked the S1P-induced action. RT-PCR revealed the presence of the S1P2 in ICC. Calphostin C (a protein kinase C inhibitor), NS-398 (a cyclooxygenase-2 inhibitor), PD 98059 (a p42/44 inhibitor), or SB 203580 (a p38 inhibitor) had no effects on S1P-induced action. However, c-jun NH2-terminal kinase (JNK) inhibitor II suppressed S1P-induced action. External Ca2+-free solution or thapsigargin (a Ca2+-ATPase inhibitor of endoplasmic reticulum) suppressed action of S1P on ICC. In recording of intracellular Ca2+ ([Ca2+]i) concentration using fluo-4/AM S1P increased intensity of spontaneous [Ca2+]i oscillations in ICC. These results suggest that S1P can modulate pacemaker activity of ICC through S1P2 via regulation of external and internal Ca2+ and mitogen-activated protein kinase activation.
윤평진,Shanker Prasad Parajuli,Dong Chuan Zuo,Pawan Kumar Shahi,오형중,신혜랑,Mi Jung Lee,염철호,최석,전제열 전남대학교 의과학연구소 2011 전남의대학술지 Vol.47 No.2
We studied whether nitric oxide (NO) and hydrogen sulfide (H2S) have an interaction on the pacemaker activities of interstitial cells of Cajal (ICC) from the mouse small intestine. The actions of NO and H2S on pacemaker activities were investigated by using the whole-cell patch-clamp technique and intracellular Ca2+ analysis at 30oC in cultured mouse ICC. Exogenously applied (±)-S-nitroso-N-acetylpenicillamine (SNAP),an NO donor, or sodium hydrogen sulfide (NaHS), a donor of H2S, showed no influence on pacemaker activity (potentials and currents) in ICC at low concentrations (10 μM SNAP and 100 μM NaHS), but SNAP or NaHS completely inhibited pacemaker amplitude and pacemaker frequency with increases in the resting currents in the outward direction at high concentrations (SNAP 100 μM and NaHS 1 mM). Co-treatment with 10 μM SNAP plus 100 μM NaHS also inhibited pacemaker amplitude and pacemaker frequency with increases in the resting currents in the outward direction. ODQ, a guanylate cyclase inhibitor, or glibenclamide, an ATP-sensitive K+ channel inhibitor,blocked the SNAP+NaHS-induced inhibition of pacemaker currents in ICC. Also, we found that SNAP+NaHS inhibited the spontaneous intracellular Ca2+ ([Ca2+]i) oscillations in cultured ICC. In conclusion, this study describes the enhanced inhibitory effects of NO plus H2S on ICC in the mouse small intestine. NO+H2S inhibited the pacemaker activity of ICC by modulating intracellular Ca2+. These results may be evidence of a physiological interaction of NO and H2S in ICC for modulating gastrointestinal motility.
김권영,최수진,장혁진,Dong Chuan Zuo,Pawan Kumar Shahi,Shankar Prasad Parajuli,염철호,윤평진,최석,전재열 대한약리학회 2008 The Korean Journal of Physiology & Pharmacology Vol.12 No.3
The effects of (−)-epigallocatechin gallate (EGCG) on pacemaker activities of cultured interstitial cells of Cajal (ICC) from murine small intestine were investigated using whole-cell patch-clamp technique at 30℃ and Ca²+ image analysis. ICC generated spontaneous pacemaker currents at a holding potential of −70 mV. The treatment of ICC with EGCG resulted in a dose-dependent decrease in the frequency and amplitude of pacemaker currents. SQ-22536, an adenylate cyclase inhibitor, and ODQ, a guanylate cyclase inhibitor, did not inhibit the effects of EGCG. EGCG-induced effects on pacemaker currents were not inhibited by glibenclamide, an ATP-sensitive K+ channel blocker and TEA, a Ca²+-activated K+ channel blocker. Also, we found that EGCG inhibited the spontaneous [Ca²+]i oscillations in cultured ICC. In conclusion, EGCG inhibited the pacemaker activity of ICC and reduced [Ca²+]i oscillations by cAMP-, cGMP-, ATP-sensitive K+ channel-independent manner.
Kim, Kweon-Young,Choi, Soo-Jin,Jang, Hyuk-Jin,Zuo, Dong-Chuan,Shahi, Pawan Kumar,Parajuli, Shankar Prasad,Yeum, Cheol-Ho,Yoon, Pyung-Jin,Choi, Seok,Jun, Jae-Yeoul The Korean Society of Pharmacology 2008 The Korean Journal of Physiology & Pharmacology Vol.12 No.3
The effects of (-)-epigallocatechin gallate (EGCG) on pacemaker activities of cultured interstitial cells of Cajal (ICC) from murine small intestine were investigated using whole-cell patch-clamp technique at $30^{\circ}C$ and $Ca^{2+}$ image analysis. ICC generated spontaneous pacemaker currents at a holding potential of -70 mV. The treatment of ICC with EGCG resulted in a dose-dependent decrease in the frequency and amplitude of pacemaker currents. SQ-22536, an adenylate cyclase inhibitor, and ODQ, a guanylate cyclase inhibitor, did not inhibit the effects of EGCG. EGCG-induced effects on pacemaker currents were not inhibited by glibenclamide, an ATP-sensitive $K^+$ channel blocker and TEA, a $Ca^{2+}$-activated $K^+$ channel blocker. Also, we found that EGCG inhibited the spontaneous $[Ca^{2+}]_i$ oscillations in cultured ICC. In conclusion, EGCG inhibited the pacemaker activity of ICC and reduced $[Ca^{2+}]_i$ oscillations by cAMP-, cGMP-, ATP-sensitive $K^+$ channel-independent manner.