The effects of mitochondrial inhibitors on Ca2+ signalling and electrical conductances required for pacemaking in interstitial cells of Cajal in the mouse small intestine

Drumm, Bernard T.; Sung, Tae Sik; Zheng, Haifeng; Baker, Salah A.; Koh, Sang Don; Sanders, Kenton M.

doi:10.1016/j.ceca.2018.01.003

Cited by 22 publications

(28 citation statements)

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“…For experiments involving pharmacological treatments, control video sequences were collected for 20-30 s, and then KRB solution containing the drug concentration to be tested was perfused into the bath for 12-15 min before another 20-30 s period of imaging was performed. Ca 2+ transients in myenteric ICC (ICC-MY) were quantified using particle (PTCL) analysis, as described previously (Drumm et al, 2017(Drumm et al, , 2018(Drumm et al, , 2019Zheng et al, 2018). Briefly, movies were imported into custom software (Volumetry G8d) and motion stabilized to minimize residual motion artifacts.…”

Section: Imaging and Analysis Of Ca 2+ Transientsmentioning

confidence: 99%

Na+/Ca2 + Exchange and Pacemaker Activity of Interstitial Cells of Cajal

et al. 2020

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Interstitial cells of Cajal (ICC) are pacemaker cells that generate electrical slow waves in gastrointestinal (GI) smooth muscles. Slow waves organize basic motor patterns, such as peristalsis and segmentation in the GI tract. Slow waves depend upon activation of Ca 2+-activated Cl − channels (CaCC) encoded by Ano1. Slow waves consist of an upstroke depolarization and a sustained plateau potential that is the main factor leading to excitation-contraction coupling. The plateau phase can last for seconds in some regions of the GI tract. How elevated Ca 2+ is maintained throughout the duration of slow waves, which is necessary for sustained activation of CaCC, is unknown. Modeling has suggested a role for Na + /Ca 2+ exchanger (NCX) in regulating CaCC currents in ICC, so we tested this idea on murine intestinal ICC. ICC of small and large intestine express NCX isoforms. NCX3 is closely associated with ANO1 in ICC, as shown by immunoprecipitation and proximity ligation assays (PLA). KB-R7943, an inhibitor of NCX, increased CaCC current in ICC, suggesting that NCX, acting in Ca 2+ exit mode, helps to regulate basal [Ca 2+ ] i in these cells. Shifting NCX into Ca 2+ entry mode by replacing extracellular Na + with Li + increased spontaneous transient inward currents (STICs), due to activation of CaCC. Stepping ICC from −80 to −40 mV activated slow wave currents that were reduced in amplitude and duration by NCX inhibitors, KB-R7943 and SN-6, and enhanced by increasing the NCX driving force. SN-6 reduced the duration of clustered Ca 2+ transients that underlie the activation of CaCC and the plateau phase of slow waves. Our results suggest that NCX participates in slow waves as modeling has predicted. Dynamic changes in membrane potential and ionic gradients during slow waves appear to flip the directionality of NCX, facilitating removal of Ca 2+ during the inter-slow wave interval and providing Ca 2+ for sustained activation of ANO1 during the slow wave plateau phase.

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Section: Imaging and Analysis Of Ca 2+ Transientsmentioning

confidence: 99%

Na+/Ca2 + Exchange and Pacemaker Activity of Interstitial Cells of Cajal

et al. 2020

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“…; Drumm et al . , ), ICC‐like cells (ICC‐LC) in rabbit urethra (Drumm et al . ), cardiomyocytes (Cheng et al .…”

Section: Discussionmentioning

confidence: 99%

“…Ca 2+ transients in colonic ICC-IM rarely arose from a single point in a cell but rather originated from multiple firing sites. Ca 2+ release from multiple sites of origin also occurs in ICC-DMP and ICC-MY in the small intestine (Baker et al 2016;Drumm et al 2017Drumm et al , 2018b, ICC-like cells (ICC-LC) in rabbit urethra , cardiomyocytes (Cheng et al 1993), Xenopus oocytes Sun et al 1998) and SMCs ZhuGe et al 1999;Gordienko et al 2001;Drumm et al 2018a). In some cells, Ca 2+ firing sites are believed to be due to the presence of a high density clusters of RyRs at these locations (Gordienko et al 2001 Ohi et al 2001;Bao et al 2008;Lifshitz et al 2011;Pritchard et al 2017).…”

Section: Discussionmentioning

confidence: 99%

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Ca²⁺ signalling behaviours of intramuscular interstitial cells of Cajal in the murine colon

Drumm

Hwang

Baker

et al. 2019

The Journal of Physiology

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Key points Colonic intramuscular interstitial cells of Cajal (ICC‐IM) exhibit spontaneous Ca2+ transients manifesting as stochastic events from multiple firing sites with propagating Ca2+ waves occasionally observed. Firing of Ca2+ transients in ICC‐IM is not coordinated with adjacent ICC‐IM in a field of view or even with events from other firing sites within a single cell. Ca2+ transients, through activation of Ano1 channels and generation of inward current, cause net depolarization of colonic muscles. Ca2+ transients in ICC‐IM rely on Ca2+ release from the endoplasmic reticulum via IP3 receptors, spatial amplification from RyRs and ongoing refilling of ER via the sarcoplasmic/endoplasmic‐reticulum‐Ca2+‐ATPase. ICC‐IM are sustained by voltage‐independent Ca2+ influx via store‐operated Ca2+ entry. Some of the properties of Ca2+ in ICC‐IM in the colon are similar to the behaviour of ICC located in the deep muscular plexus region of the small intestine, suggesting there are functional similarities between these classes of ICC. Abstract A component of the SIP syncytium that regulates smooth muscle excitability in the colon is the intramuscular class of interstitial cells of Cajal (ICC‐IM). All classes of ICC (including ICC‐IM) express Ca2+‐activated Cl− channels, encoded by Ano1, and rely upon this conductance for physiological functions. Thus, Ca2+ handling in ICC is fundamental to colonic motility. We examined Ca2+ handling mechanisms in ICC‐IM of murine proximal colon expressing GCaMP6f in ICC. Several Ca2+ firing sites were detected in each cell. While individual sites displayed rhythmic Ca2+ events, the overall pattern of Ca2+ transients was stochastic. No correlation was found between discrete Ca2+ firing sites in the same cell or in adjacent cells. Ca2+ transients in some cells initiated Ca2+ waves that spread along the cell at ∼100 µm s−1. Ca2+ transients were caused by release from intracellular stores, but depended strongly on store‐operated Ca2+ entry mechanisms. ICC Ca2+ transient firing regulated the resting membrane potential of colonic tissues as a specific Ano1 antagonist hyperpolarized colonic muscles by ∼10 mV. Ca2+ transient firing was independent of membrane potential and not affected by blockade of L‐ or T‐type Ca2+ channels. Mechanisms regulating Ca2+ transients in the proximal colon displayed both similarities to and differences from the intramuscular type of ICC in the small intestine. Similarities and differences in Ca2+ release patterns might determine how ICC respond to neurotransmission in these two regions of the gastrointestinal tract.

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“…Video recordings of Ca 2+ transients in ICC-SS were collected via fluorescence microscopy aiming to better understand the role of these cells with respect to regulating LSMCs. ICC-SS express the Ca 2+ -activated Cl − conductance, Ano1, selectively (Gomez-Pinilla et al 2009;Blair et al 2012a) and an evaluation of the specific properties and mechanisms of Ca 2+ transients, shown in other ICC to regulate the activation of Ano1 (Zhu et al 2015;Baker et al 2016;Drumm et al 2017Drumm et al , 2018bDrumm et al , 2019bDrumm et al , 2019c, provides a novel means of investigating the role ICC-SS in LM motility.…”

Section: Introductionmentioning

confidence: 99%

Pacemaker function and neural responsiveness of subserosal interstitial cells of Cajal in the mouse colon

Drumm

Rembetski

Messersmith

et al. 2020

The Journal of Physiology

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Key pointsr Rhythmic action potentials and intercellular Ca 2+ waves are generated in smooth muscle cells of colonic longitudinal muscles (LSMC).r Longitudinal muscle excitability is tuned by input from subserosal ICC (ICC-SS), a population of ICC with previously unknown function.r ICC-SS express Ano1 channels and generate spontaneous Ca 2+ transients in a stochastic manner.r Release of Ca 2+ and activation of Ano1 channels causes depolarization of ICC-SS and LSMC, leading to activation of L-type Ca 2+ channels, action potentials, intercellular Ca 2+ waves and contractions in LSMC.r Nitrergic neural inputs regulate the Ca 2+ events in ICC-SS. r Pacemaker activity in longitudinal muscle is an emergent property as a result of integrated processes in ICC-SS and LSMC.Abstract Much is known about myogenic mechanisms in circular muscle (CM) in the gastrointestinal tract, although less is known about longitudinal muscle (LM). Two Ca 2+ signalling behaviours occur in LM: localized intracellular waves not causing contractions and intercellular waves leading to excitation-contraction coupling. An Ano1 channel antagonist inhibited intercellular Ca 2+ waves and LM contractions. Ano1 channels are expressed by interstitial cells of Cajal (ICC) but not by smooth muscle cells (SMCs). We investigated Ca 2+ signalling in a novel population of ICC that lies along the subserosal surface of LM (ICC-SS) in mice expressing GCaMP6f in ICC. ICC-SS fired stochastic localized Ca 2+ transients. Such events have been linked to activation of Ano1 channels in ICC. Ca 2+ transients in ICC-SS occurred by release from stores most probably via inositol trisphosphate receptors. This activity relied on influx via store-operated Bernard T. Drumm received his PhD in Physiology in 2013. His research investigates how Ca 2+ signalling impacts the functions of visceral smooth muscle organs in the gastrointestinal and urinary tracts. His doctoral work, studying Ca 2+ wave propagation in urethral cells, was followed by a postdoctoral position and later research track faculty position at the University of Nevada, Reno (UNR), where he studied the regulation of pacemaker and neuroeffector mechanisms in gastrointestinal interstitial cells. Dr Drumm took up a position as Lecturer in the

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The effects of mitochondrial inhibitors on Ca2+ signalling and electrical conductances required for pacemaking in interstitial cells of Cajal in the mouse small intestine

Cited by 22 publications

References 74 publications

Na+/Ca2 + Exchange and Pacemaker Activity of Interstitial Cells of Cajal

Na+/Ca2 + Exchange and Pacemaker Activity of Interstitial Cells of Cajal

Ca²⁺ signalling behaviours of intramuscular interstitial cells of Cajal in the murine colon

Pacemaker function and neural responsiveness of subserosal interstitial cells of Cajal in the mouse colon

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The effects of mitochondrial inhibitors on Ca2+ signalling and electrical conductances required for pacemaking in interstitial cells of Cajal in the mouse small intestine

Cited by 22 publications

References 74 publications

Na+/Ca2 + Exchange and Pacemaker Activity of Interstitial Cells of Cajal

Na+/Ca2 + Exchange and Pacemaker Activity of Interstitial Cells of Cajal

Ca2+ signalling behaviours of intramuscular interstitial cells of Cajal in the murine colon

Pacemaker function and neural responsiveness of subserosal interstitial cells of Cajal in the mouse colon

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Ca²⁺ signalling behaviours of intramuscular interstitial cells of Cajal in the murine colon