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Mitochondrial Ca²⁺ uptake and release influence metabotropic and ionotropic cytosolic Ca²⁺ responses in rat oligodendrocyte progenitors

Peter B. Simpson and James T. Russell

1. Many physiologically important activities of oligodendrocyte progenitor cells (O-2A cells), including proliferation, migration and differentiation, are regulated by cytosolic Ca²⁺ signals. However, little is known concerning the mechanisms of Ca²⁺ signalling in this cell type. We have studied the interactions between Ca²⁺ entry, Ca²⁺ release from endoplasmic reticulum and Ca²⁺ regulation by mitochondria in influencing cytosolic Ca²⁺ responses in O-2A cells.

2. Methacholine (MCh; 100 µM) activated Ca²⁺ waves that propagated from several initiation sites along O-2A processes.

3. During a Ca²⁺ wave evoked by MCh, mitochondrial membrane potential was often either depolarized (21 % of mitochondria) or hyperpolarized (20 % of mitochondria), as measured by changes in the fluorescence of 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazole carbocyanine iodide (JC-1).

4. Stimulation with kainate (100 µM) evoked a slowly rising, sustained cytosolic Ca²⁺ elevation in O-2A cells. This also, in some cases, resulted in either a depolarization (15 % of mitochondria) or hyperpolarization (12 % of mitochondria) of mitochondrial membrane potential.

5. Simultaneous measurement of cytosolic (fluo-3 AM) and mitochondrial (rhod-2 AM) Ca²⁺ responses revealed that Ca²⁺ elevations in the cytosol evoked by either MCh or kainate were translated into long-lasting Ca²⁺ elevations in subpopulations of mitochondria. In some mitochondria, Ca²⁺ signals appeared to activate Ca²⁺ release into the cytosol.

6. Inhibition of the mitochondrial Na⁺-Ca²⁺ exchanger by CGP-37157 (25 µM) decreased kainate Ca²⁺ response amplitude and increased the rate of return of the response to basal Ca²⁺ levels.

7. Thus, both ionotropic and metabotropic stimulation evoke changes in mitochondrial membrane potential and Ca²⁺ levels in O-2A cells. Ca²⁺ uptake into some mitochondria is activated by Ca²⁺ entry into cells or release from stores. Mitochondrial Ca²⁺ release appears to play a key role in shaping kainate-evoked Ca²⁺ responses.

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