A Novel Pacemaker Mechanism Drives Gastrointestinal Rhythmicity

Physiology ◽  
2000 ◽  
Vol 15 (6) ◽  
pp. 291-298 ◽  
Author(s):  
Kenton M. Sanders ◽  
Tamás Ördög ◽  
Sang Don Koh ◽  
Sean M. Ward
Keyword(s):  
Endoplasmic Reticulum ◽  
Gastrointestinal Tract ◽  
Interstitial Cells Of Cajal ◽  
Interstitial Cells ◽  
Pacemaker Activity ◽  
Cation Conductance ◽  
Inward Currents ◽  
Cells Of Cajal ◽  
Pacemaker Currents

Electric pacemaker activity drives peristaltic and segmental contractions in the gastrointestinal tract. Interstitial cells of Cajal (ICC) are responsible for spontaneous pacemaker activity. ICC remain rhythmic in culture and generate voltage-independent inward currents via a nonselective cation conductance. Ca2+ release from endoplasmic reticulum and uptake by mitochondria initiates pacemaker currents. This novel mechanism provides the basis for electric rhythmicity in gastrointestinal muscles.

scholarly journals Intracellular Ca2+ release from endoplasmic reticulum regulates slow wave currents and pacemaker activity of interstitial cells of Cajal

2015 ◽  
Vol 308 (8) ◽  
pp. C608-C620 ◽  
Author(s):  
Mei Hong Zhu ◽  
Tae Sik Sung ◽  
Kate O'Driscoll ◽  
Sang Don Koh ◽  
Kenton M. Sanders
Keyword(s):  
Slow Wave ◽  
Interstitial Cells Of Cajal ◽  
Ryanodine Receptors ◽  
Interstitial Cells ◽  
Pacemaker Activity ◽  
Current Clamp ◽  
Anoctamin 1 ◽  
Intracellular Ca ◽  
Inward Currents ◽  
Cells Of Cajal

Interstitial cells of Cajal (ICC) provide pacemaker activity in gastrointestinal muscles that underlies segmental and peristaltic contractions. ICC generate electrical slow waves that are due to large-amplitude inward currents resulting from anoctamin 1 (ANO1) channels, which are Ca2+-activated Cl− channels. We investigated the hypothesis that the Ca2+ responsible for the stochastic activation of ANO1 channels during spontaneous transient inward currents (STICs) and synchronized activation of ANO1 channels during slow wave currents comes from intracellular Ca2+ stores. ICC, obtained from the small intestine of Kit +/copGFP mice, were studied under voltage and current clamp to determine the effects of blocking Ca2+ uptake into stores and release of Ca2+ via inositol 1,4,5-trisphosphate (IP3)-dependent and ryanodine-sensitive channels. Cyclocpiazonic acid, thapsigargin, 2-APB, and xestospongin C inhibited STICs and slow wave currents. Ryanodine and tetracaine also inhibited STICs and slow wave currents. Store-active compounds had no direct effects on ANO1 channels expressed in human embryonic kidney-293 cells. Under current clamp, store-active drugs caused significant depolarization of ICC and reduced spontaneous transient depolarizations (STDs). After block of ryanodine receptors with ryanodine and tetracaine, repolarization did not restore STDs. ANO1 expressed in ICC has limited access to cytoplasmic Ca2+ concentration, suggesting that pacemaker activity depends on Ca2+ dynamics in restricted microdomains. Our data from studies of isolated ICC differ somewhat from studies on intact muscles and suggest that release of Ca2+ from both IP3 and ryanodine receptors is important in generating pacemaker activity in ICC.

scholarly journals Na+-K+-Cl− cotransporter (NKCC) maintains the chloride gradient to sustain pacemaker activity in interstitial cells of Cajal

2016 ◽  
Vol 311 (6) ◽  
pp. G1037-G1046 ◽  
Author(s):  
Mei Hong Zhu ◽  
Tae Sik Sung ◽  
Masaaki Kurahashi ◽  
Lauren E. O'Kane ◽  
Kate O'Driscoll ◽  
...  
Keyword(s):  
Slow Wave ◽  
Interstitial Cells Of Cajal ◽  
High Current Density ◽  
Reversal Potential ◽  
Interstitial Cells ◽  
Slow Waves ◽  
Hek293 Cells ◽  
Pacemaker Activity ◽  
Inward Currents ◽  
Cells Of Cajal

Interstitial cells of Cajal (ICC) generate electrical slow waves by coordinated openings of ANO1 channels, a Ca2+-activated Cl− (CaCC) conductance. Efflux of Cl− during slow waves must be significant, as there is high current density during slow-wave currents and slow waves are of sufficient magnitude to depolarize the syncytium of smooth muscle cells and PDGFRα+ cells to which they are electrically coupled. We investigated how the driving force for Cl− current is maintained in ICC. We found robust expression of Slc12a2 (which encodes an Na+-K+-Cl− cotransporter, NKCC1) and immunohistochemical confirmation that NKCC1 is expressed in ICC. With the use of the gramicidin permeabilized-patch technique, which is reported to not disturb [Cl−]i, the reversal potential for spontaneous transient inward currents ( ESTICs) was −10.5 mV. This value corresponds to the peak of slow waves when they are recorded directly from ICC in situ. Inhibition of NKCC1 with bumetanide shifted ESTICs to more negative potentials within a few minutes and reduced pacemaker activity. Bumetanide had no direct effects on ANO1 or CaV3.2 channels expressed in HEK293 cells or L-type Ca2+ currents. Reducing extracellular Cl− to 10 mM shifted ESTICs to positive potentials as predicted by the Nernst equation. The relatively rapid shift in ESTICs when NKCC1 was blocked suggests that significant changes in the transmembrane Cl− gradient occur during the slow-wave cycle, possibly within microdomains formed between endoplasmic reticulum and the plasma membrane in ICC. Recovery of Cl− via NKCC1 might have additional consequences on shaping the waveforms of slow waves via Na+ entry into microdomains.

scholarly journals SOCE mediated by STIM and Orai is essential for pacemaker activity in the interstitial cells of Cajal in the gastrointestinal tract

2018 ◽  
Vol 11 (534) ◽  
pp. eaaq0918 ◽  
Author(s):  
Haifeng Zheng ◽  
Bernard T. Drumm ◽  
Scott Earley ◽  
Tae Sik Sung ◽  
Sang Don Koh ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Interstitial Cells Of Cajal ◽  
Interstitial Cells ◽  
Pacemaker Activity ◽  
Cells Of Cajal

scholarly journals Expression and function of a T-type Ca2+ conductance in interstitial cells of Cajal of the murine small intestine

2014 ◽  
Vol 306 (7) ◽  
pp. C705-C713 ◽  
Author(s):  
Haifeng Zheng ◽  
Kyung Sik Park ◽  
Sang Don Koh ◽  
Kenton M. Sanders
Keyword(s):  
Interstitial Cells Of Cajal ◽  
Low Voltage ◽  
Interstitial Cells ◽  
Slow Waves ◽  
Pacemaker Activity ◽  
Inward Current ◽  
Voltage Dependent ◽  
Inward Currents ◽  
Cells Of Cajal ◽  
Upstroke Velocity

Interstitial cells of Cajal (ICC) generate slow waves in gastrointestinal (GI) muscles. Previous studies have suggested that slow wave generation and propagation depends on a voltage-dependent Ca2+ entry mechanism with the signature of a T-type Ca2+ conductance. We studied voltage-dependent inward currents in isolated ICC. ICC displayed two phases of inward current upon depolarization: a low voltage-activated inward current and a high voltage-activated current. The latter was of smaller current density and blocked by nicardipine. Ni2+ (30 μM) or mibefradil (1 μM) blocked the low voltage-activated current. Replacement of extracellular Ca2+ with Ba2+ did not affect the current, suggesting that either charge carrier was equally permeable. Half-activation and half-inactivation occurred at −36 and −59 mV, respectively. Temperature sensitivity of the Ca2+ current was also characterized. Increasing temperature (20–30°C) augmented peak current from −7 to −19 pA and decreased the activation time from 20.6 to 7.5 ms [temperature coefficient (Q10) = 3.0]. Molecular studies showed expression of Cacna1g (Cav3.1) and Cacna1h (Cav3.2) in ICC. The temperature dependence of slow waves in intact jejunal muscles of wild-type and Cacna1h −/− mice was tested. Reducing temperature decreased the upstroke velocity significantly. Upstroke velocity was also reduced in muscles of Cacna1h −/− mice, and Ni2+ or reduced temperature had little effect on these muscles. Our data show that a T-type conductance is expressed and functional in ICC. With previous studies our data suggest that T-type current is required for entrainment of pacemaker activity within ICC and for active propagation of slow waves in ICC networks.

scholarly journals Effects of Lubiprostone on Pacemaker Activity of Interstitial Cells of Cajal from the Mouse Colon

2014 ◽  
Vol 18 (4) ◽  
pp. 341 ◽  
Author(s):  
Han-Yi Jiao ◽  
Dong Hyun Kim ◽  
Jung Suk Ki ◽  
Kwon Ho Ryu ◽  
Seok Choi ◽  
...  
Keyword(s):  
Interstitial Cells Of Cajal ◽  
Interstitial Cells ◽  
Pacemaker Activity ◽  
Mouse Colon ◽  
Cells Of Cajal

CD34 immunoreactivity and interstitial cells of Cajal in the human and mouse gastrointestinal tract

2000 ◽  
Vol 302 (2) ◽  
pp. 145-153 ◽  
Author(s):  
Jean-Marie Vanderwinden ◽  
Jüri J. Rumessen ◽  
Marc-Henri De Laet ◽  
Jean-Jacques Vanderhaeghen ◽  
Serge N. Schiffmann
Keyword(s):  
Gastrointestinal Tract ◽  
Interstitial Cells Of Cajal ◽  
Interstitial Cells ◽  
Cells Of Cajal ◽  
Human And Mouse
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