Inositol 1,4,5-trisphosphate may regulate rat brain Cai++ by inhibiting membrane bound Na(+)-Ca++ exchanger.
The role of inositol 1,4,5-trisphosphate (1,4,5-IP3) in regulating cytosolic Ca++ by stimulating Ca++ release from intracellular organelles is well established. However, other modes of intracellular Ca++ regulation by 1,4,5-IP3 have not been determined. To determine if 1,4,5-IP3 may regulate cell cytosolic Ca++ by acting on plasma membrane bound Na(+)-Ca++ exchanger, we investigated Ca++ transport in synaptosomes using 45Ca++ as tracer. In the presence of either an inhibitor of voltage gated Na+ channels (tetrodotoxin) or the K+ ionophore (valinomycin), Ca++ uptake was significantly inhibited (P less than 0.05) by 1,4,5-IP3 in a concentration dependent manner, with half-maximal inhibition occurring at submicromolar concentrations between 10(-9) M and 10(-10) M 1,4,5-IP3. Similarly, Ca++ efflux by the exchanger was significantly inhibited 40% by 1,4,5-IP3. The inhibitory effect of 1,4,5-IP3 on the Na(+)-Ca++ exchanger was observed in the presence of Ca++ channel blockers, and in vesicles pretreated with caffeine to deplete the 1,4,5-IP3-sensitive stores of Ca++. These results suggest that during signal transduction in brain, 1,4,5-IP3 may increase cytosolic [Ca++] in part by inhibiting the Na(+)-Ca++ exchanger and thus, Ca++ efflux from cell.
Fraser
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CL
Department of Medicine, Veterans Affairs Medical Center, San Francisco, California 94121.
Sarnacki
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D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005711:Gallopamil / Q000494:pharmacology; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000502:physiology*; D007295:Inositol Phosphates / Q000494:pharmacology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D015398:Signal Transduction; D015222:Sodium Channels / Q000187:drug effects; D019831:Sodium-Calcium Exchanger; D013574:Synaptosomes / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology
D015220:Calcium Channels; D002352:Carrier Proteins; D007295:Inositol Phosphates; D015222:Sodium Channels; D019831:Sodium-Calcium Exchanger; D005711:Gallopamil; D002110:Caffeine; D013779:Tetrodotoxin; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium