Mitochondrial calcium handling within the interstitial cells of Cajal

Abstract

dynamics within pacemaker cells of the gastrointestinal (GI) tract, the interstitial cells of Cajal (ICC) (a glossary of all abbreviations can be found in Table 1). They were established as the GI pacemakers (44) long after their initial discovery in the 19th century (12), and the performance and structure of the ICC network are intimately related to proper GI motility and function. Disruption of the network can result in conditions such as constipation, gastroparesis, or achalasia (33,66). The pacemaking signals themselves in the ICC are membrane depolarizations also known as slow waves (SW) that rhythmically occur at different intrinsic frequencies depending on species and tissue type. They can range in humans from three cycles per minute (cpm) in the stomach to 8 -12 cpm in the intestine (43) (63), and these depolarizations coordinate contractions in surrounding smooth muscle tissue. The physiological location, spatial scales, and the relative paucity of experimental data of the ICC continue to challenge experimentalists and theoretical explorations. It is known, however, that unitary potentials, or spontaneous-transient depolarizations (SD), of the ICC membrane generate the SW in some way, yet the mechanisms responsible for producing SD themselves are not clearly understood. Membrane channels in the ICC such as the nonspecific cation conductance (NSCC) (63) and the Ca 2ϩ -activated chloride channels (the ANO1) (84) are likely involved in SD production, but their roles are unclear.Daniel et al. (20) showed depletions of the endoplasmic reticulum (ER) Ca 2ϩ reservoir reduce the frequency of intestinal smooth muscle contractions (19) and suggested that the pacing of ICC is related to recycling Ca 2ϩ into the ER from sequestered stores in caveolae (20). It is known that Ca 2ϩ transport via the intracellular inositol-trisphosphate (IP 3 ) receptors (IP 3 R) on the ER into the cytosol (73, 78) and mitochondria (MT) uptake of cytosolic Ca 2ϩ (38, 78) is involved in generation of SW activity. Disruption of MT sodium-calcium exchangers (NCX) reduces the frequency of the Ca 2ϩ oscillations (45), albeit modestly and eventually on a time scale of minutes; notably, the MT NCX are also essential to the function of store-operated Ca 2ϩ entry (SOCE) (52). We thus hypothesize that depletions of the ER Ca 2ϩ reservoir and subsequent activation of SOCE are fundamental to pacemaking of the ICC. The eventual depletion of ER Ca 2ϩ stores and activation of ER SOCE mechanisms, such as the stromal interaction molecules (STIM) on the ER membrane sensing intraluminal ER Ca 2ϩ and their plasma membrane (PM) complements, either the Orai or transient receptor potential channels (TRPC) (11), are essential to intracellular ICC Ca 2ϩ oscillations. These Ca 2ϩ oscillations would then, in turn, determine the electrical SW activity observed by interaction with Ca 2ϩ -sensitive ion channels. Depletions of the ER Ca 2ϩ reservoir by virtue of the ER-MT Ca 2ϩ transport dynamic in a biophysically based model are of comparable timescales to those ob...

Normal and abnormal electrical propagation in the small intestine

“…, Corrias & Buist ) and recent modelling of intracellular events in these ICC's (Lees‐Green et al . , Means & Cheng ) may ultimately shed some light in this very long tunnel.…”

“…It is fair to say, however, that the exact mechanism of slow wave initiation and propagation has still, to date, not been fully resolved , Sanders et al 2014. Potentially, the development of ever more sophisticated modelling studies of the slow wave (Aliev et al 2000, Corrias & Buist 2008 and recent modelling of intracellular events in these ICC's (Lees-Green et al 2014, Means & Cheng 2014) may ultimately shed some light in this very long tunnel.…”

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

“…Thus, the exact role of mitochondria in pacemaker activity, if any, remains uncertain. It appears that all previous work on mitochondrial function in ICC have relied upon some or all of the pharmacological tools tested in the current study [23–25,55,56,62,63] and therefore models of pacemaker activity that have incorporated mitochondrial Ca 2+ uptake as a contributing variable [66–69] may require reconsideration. However, the fact remains that ICC contain an abundance of mitochondria [18–20], and thus mitochondria may be important in sustaining the rigorous electrical behaviours of pacemaker cells.…”

Interstitial Cells of Cajal: Potential Targets for Functional Dyspepsia Treatment Using Medicinal Natural Products

“…In fact, a relatively low concentration of NO, as a neurotransmitter, is essential for ICCs to function properly [ 65 ], whereas a higher concentration or long-term exposure to NO can induce ICC damage [ 66 ]. The high density of mitochondria in ICCs can explain the increased susceptibility to oxidative stress conditions [ 67 , 68 ]. As mentioned above, mitochondria are essential for Ca 2+ handling within ICCs to generate slow waves [ 69 ].…”