Purified reconstituted inositol 1,4,5-trisphosphate receptors. Thiol reagents act directly on receptor protein.
Thimerosal, a sulfhydryl oxidizing reagent, has been shown to induce Ca2+ mobilization in several cell types and to increase the sensitivity of intracellular Ca2+ stores to inositol 1,4,5-trisphosphate (IP3). Using purified IP3 receptor (IP3R) protein reconstituted in vesicles, we demonstrate pronounced stimulation by thimerosal of its Ca2+ channel activity. Effects of thimerosal are dependent on the redox state of the receptor, implying an action of thimerosal on a critical sulfhydryl group(s) of IP3R. Thimerosal enhances the affinity of IP3R for IP3 binding. The manner in which thimerosal modulates IP3R responsiveness to IP3 provides evidence for receptor heterogeneity with implications for mechanisms of quantal Ca2+ release. These results clarify regulation of IP3R activity by redox modulation.
Kaplin
A I
AI
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Ferris
C D
CD
Voglmaier
S M
SM
Snyder
S H
SH
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002875:Chromosomes; D004270:DNA, Circular; D016054:DNA, Protozoan / Q000032:analysis; D005784:Gene Amplification; D017125:Genes, Protozoan; D007168:IMP Dehydrogenase / Q000235:genetics*; D008969:Molecular Sequence Data; D009173:Mycophenolic Acid / Q000494:pharmacology; D010641:Phenotype; D017386:Sequence Homology, Amino Acid; D014347:Trypanosoma brucei gambiense / Q000187:drug effects / Q000201:enzymology*
D004270:DNA, Circular; D016054:DNA, Protozoan; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid