Pacemaking in interstitial cells of Cajal depends upon calcium handling by endoplasmic reticulum and mitochondria

Ward, Sean M.; Ördög, Tamás; Koh, Sang Don; Baker, Salah A.; Jun, Jae Yeoul; Amberg, Gregory C.; Monaghan, Kevin; Sanders, Kenton M.

doi:10.1111/j.1469-7793.2000.t01-1-00355.x

Cited by 280 publications

(379 citation statements)

References 29 publications

(43 reference statements)

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“…Washout of the medium conditioned by the transformed cells by perfusion with fresh serum-free medium causes the cells to slowly repolarize, and, preceded by a short period of fast small-amplitude spiking of their membrane potential ("fast oscillating state"), to regain spontaneous repetitive action potential firing activity ("AP-firing state") similar to that of the contact inhibited cells. These phenomena have been described in detail (23) and are very similar to the behavior of other cell types with calcium oscillations and action potential firing, such as interstitial cells of Cajal (24) and hepatocytes (25).…”

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confidence: 68%

Hysteresis and Bistability in a Realistic Cell Model for Calcium Oscillations and Action Potential Firing

et al. 2007

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Many cell types exhibit oscillatory activity, such as repetitive action potential firing due to the Hodgkin-Huxley dynamics of ion channels in the cell membrane or reveal intracellular inositol triphosphate (IP 3 ) mediated calcium oscillations (CaOs) by calcium-induced calcium release channels (IP 3 -receptor) in the membrane of the endoplasmic reticulum (ER). The dynamics of the excitable membrane and that of the IP 3 -mediated CaOs have been the subject of many studies. However, the interaction between the excitable cell membrane and IP 3 -mediated CaOs, which are coupled by cytosolic calcium which affects the dynamics of both, has not been studied. This study for the first time applied stability analysis to investigate the dynamic behavior of a model, which includes both an excitable membrane and an intracellular IP 3 -mediated calcium oscillator. Taking the IP 3 concentration as a control parameter, the model exhibits a novel rich spectrum of stable and unstable states with hysteresis. The four stable states of the model correspond in detail to previously reported growth-state dependent states of the membrane potential of normal rat kidney fibroblasts in cell culture. The hysteresis is most pronounced for experimentally observed parameter values of the model, suggesting a functional importance of hysteresis. This study shows that the four growth-dependent cell states may not reflect the behavior of cells that have differentiated into different cell types with different properties, but simply reflect four different states of a single cell type, that is characterized by a single model.Key words: Hysteresis; Bistability; Calcium Oscillations; Cell Signaling 2 Complexity and multiple transitions among behaviorial states are ubiquitous in biological systems (1, 2). In physics instabilities and hysteresis are well known to play an important role in collective properties and have been studied since many years (3,4,5,6). Recently, multi-stability with hysteresis has also awakened a large interest in biological systems (7).Instabilities, for instance, are crucial for efficient information processing in the brain, such as in odor encoding (8,9). Moreover, unstable dynamic attractors have been demonstrated in cortical networks, with critical relevance to working memory and attention (10,11,12). In a wide sense, multistable systems allow changes among different stable solutions where the system takes advantage of instabilities as gateways to switch between different stable branches (7). Bistability driven by instabilities prevents the system from reaching intermediate states, e.g. partial mitosis. Hysteresis prevents the system from changing its state when parameter values, that characterize the system, vary. This is of relevance, for instance, in cell mitosis.Once initiated, mitosis should not be terminated before completion (13). Thus, hysteresis may lock the cell into a fixed state, preventing it from sliding back to another state (14).At the level of cell networks, multistability, and in particular bista...

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confidence: 68%

Hysteresis and Bistability in a Realistic Cell Model for Calcium Oscillations and Action Potential Firing

et al. 2007

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“…A pacemaker role is now generally accepted for enteric ICC, which generate electrical rhythmicity in the gastrointestinal tract [22,23,107]. Why should not t-ICC be responsible for the human fallopian tube peristalsis ?…”

Section: T-icc: Network For Pacemakingmentioning

confidence: 99%

Novel type of interstitial cell (Cajal-like) in human fallopian tube

et al. 2005

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We describe here ‐ presumably for the first time‐a Cajal‐like type of tubal interstitial cells (t‐ICC), resembling the archetypal enteric ICC. t‐ICC were demonstrated in situ and in vitro on fresh preparations (tissue cryosections and primary cell cultures) using methylene‐blue, crystal‐violet, Janus‐Green B or Mito Tracker‐Green FM Probe vital stainings. Also, t‐ICC were identified in fixed specimens by light microscopy (methylene‐blue, Giemsa, trichrome stainings, Gomori silver‐impregnation) or transmission electron microscopy (TEM). The positive diagnosis of t‐ICC was strengthened by immunohistochemistry (IHC; CD117/c‐kit+ and other 14 antigens) and immunofluorescence (IF; CD117/c‐kit+ and other 7 antigens). The spatial density of t‐ICC (ampullar‐segment cryosections) was 100–150 cells/mm2. Non‐conventional light microscopy (NCLM) of Epon semithin‐sections revealed a network‐like distribution of t‐ICC in lammina propria and smooth muscle meshwork. t‐ICC appeared located beneath of epithelium, in a 10–15μ thick ‘belt’, where 18±2% of cells were t‐ICC. In the whole lamina propria, t‐ICC were about 9%, and in muscularis ∼7%. In toto, t‐ICC represent ∼8% of subepithelial cells, as counted by NCLM. In vitro, t‐ICC were 9.9±0.9% of total cell population. TEM showed that the diagnostic ‘gold standard’ (Huizinga et al., 1997) is fulfilled by ‘our’ t‐ICC. However, we suggest a ‘platinum standard’, adding a new defining criterion ‐ characteristic cytoplasmic processes (number: 1–5; length: tens of μm; thickness: ±0.5μ; aspect: moniliform; braching: dichotomous; organization: network, labyrinthic‐system). Quantitatively, the ultrastructural architecture of t‐ICC is: nucleus, 23.6±3.2% of cell volume, with heterochromatin 49.1±3.8%; mitochondria, 4.8±1.7%; rough and smooth endoplasmic‐reticulum (1.1±0.6%, 1.0±0.2%, respectively); caveolae, 3.4±0.5%. We found more caveolae on the surface of cell processes versus cell body, as confirmed by IF for caveolins. Occasionally, the so‐called ‘Ca2+‐release units’ (subplasmalemmal close associations of caveolae+endoplasmic reticulum±mitochondria) were detected in the dilations of cell processes. Electrophysiological single unit recordings of t‐ICC in primary cultures indicated sustained spontaneous electrical activity (amplitude of field potentials: 57.26±6.56mV). Besides the CD117/c‐kit marker, t‐ICC expressed variously CD34, caveolins 1&2, α‐SMA, S‐100, vimentin, nestin, desmin, NK‐1. t‐ICC were negative for: CD68, CD1a, CD62P, NSE, GFAP, chromogranin‐A, PGP9.5, but IHC showed the possible existence of (neuro)endocrine cells in tubal interstitium. We call them ‘JF cells’. In conclusion, the identification of t‐ICC might open the door for understanding some tubal functions, e.g. pace‐making/peristaltism, secretion (auto‐, juxta‐ and/or paracrine), regulation of neurotransmission (nitrergic/purinergic) and intercellular signaling, via the very long processes. Furthermore, t‐ICC might even be uncommitted bipotential progenitor cells.

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“…The pacemaker mechanism has been shown to involve rhythmic oscillations in intracellular calcium concentration ([Ca 2ϩ ] i ) in a compartment near the plasma membrane that controls the open probability of channels responsible for pacemaker currents. This mechanism involves Ca 2ϩ release from D-myo-inositol 1,4,5-trisphosphate (IP 3 ) receptor-operated stores and uptake of Ca 2ϩ by mitochondria (26). Mitochondrial Ca 2ϩ uptake activates voltage-independent, Ca 2ϩ -inhibited, nonselective cation channels with a unitary conductance of 13 pS (10).…”

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confidence: 99%

TRPC4 currents have properties similar to the pacemaker current in interstitial cells of Cajal

Walker

Koh

Sergeant

et al. 2002

American Journal of Physiology-Cell Physiology

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Interstitial cells of Cajal (ICC) are the pacemaker cells responsible for the generation and propagation of electrical slow waves in phasic muscles of the gastrointestinal (GI) tract. The pacemaker current that initiates each slow wave derives from a calcium-inhibited, voltage-independent, nonselective cation channel. This channel in ICC displays properties similar to that reported for the transient receptor potential (TRP) family of nonselective cation channels, particularly those seen for TRPC3 and TRPC4. We have identified transcripts for TRPC4 in individually isolated ICC and have cloned the two alternatively spliced forms of TRPC4, TRPC4α and TRPC4β, from GI muscles. TRPC4β is missing an 84-amino acid segment from the carboxy terminus. Expression of either form using the whole cell patch-clamp technique led to calcium-inhibited, nonselective cation channels as determined by N-methyl-d-glucamine replacement experiments and BAPTA dialysis. Expression of TRPC4β channels recorded at the whole cell level had characteristics similar to the nonselective cation current in ICC. The single-channel conductance of TRPC4β was determined to be 17.5 pS. Application of calmidazolium to cells expressing TRPC4β led to a significant increase in the inward current of these cells at both the whole cell and single-channel level, and currents were sensitive to block by 10 μM lanthanum, niflumic acid, and DIDS. Comparison of the properties reported for the nonselective cation current in ICC and those identified here for TRPC4β led us to conclude that a TRPC4-like current encodes the plasmalemmal pacemaker current in murine small intestine.

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Pacemaking in interstitial cells of Cajal depends upon calcium handling by endoplasmic reticulum and mitochondria

Cited by 280 publications

References 29 publications

Hysteresis and Bistability in a Realistic Cell Model for Calcium Oscillations and Action Potential Firing

Hysteresis and Bistability in a Realistic Cell Model for Calcium Oscillations and Action Potential Firing

Novel type of interstitial cell (Cajal-like) in human fallopian tube

TRPC4 currents have properties similar to the pacemaker current in interstitial cells of Cajal

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