The inositol 1,4,5-trisphosphate receptor of cerebellum. Mn2+ permeability and regulation by cytosolic Mn2+.
The inositol 1,4,5-trisphosphate receptor (InsP3R), an intracellular calcium release channel, is found in virtually all cells and is abundant in the cerebellum. We used Mn2+ as a tool to study two aspects of the cerebellar InsP3R. First, to investigate the structure of the ion pore, Mn2+ permeation through the channel was determined. We found that Mn2+ can pass through the InsP3R; the selectivity sequence for divalent cations is Ba2+ > Sr2+ > Ca2+ > Mg2+ > Mn2+. Second, to begin characterization of the cytosolic regulatory sites responsible for the Ca(2+)-dependent modulation of InsP3R function, the ability of Mn2+ to replace Ca2+ was investigated. We show that Mn2+, as Ca2+, modulates InsP3R activity with a bell-shaped dependence where the affinity of the activation site of the InsP3R is similar for both ions, but higher concentrations of Mn2+ were necessary to inhibit the channel. These results suggest that the two regulatory sites are structurally distinct. Our findings are also important for the understanding of cellular responses when Mn2+ is used to quench the intracellular fluorescence of Ca2+ indicator dyes.
Striggow
F
F
Department of Physiology, University of Connecticut Health Center, Farmington 06030-3505, USA, fstriggo@neuron.uchc.edu
Ehrlich
B E
BE
D000818:Animals; D015220:Calcium Channels / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D002531:Cerebellum / Q000737:chemistry* / Q000187:drug effects; D004285:Dogs; D007202:Indicators and Reagents; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008345:Manganese / Q000493:pharmacokinetics* / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010539:Permeability / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*
D015220:Calcium Channels; D007202:Indicators and Reagents; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D008345:Manganese