Involvement of the ryanodine-sensitive Ca2+ store in GLP-1-induced Ca2+ oscillations in insulin-secreting HIT cells.

We investigated intracellular Ca(2+) (Ca(2+)) oscillations evoked by glucagon-like peptide 1 (GLP-1) in relation to the ryanodine receptor (RyR) and Ca(2+)-induced Ca(2+)release (CICR) mechanism in pancreatic B cell HIT. GLP-1 produced Ca(2+) oscillations in the cells, both in media with and without Ca(2+), an effect inhibited by ruthenium red and mimicked by 8-Br-cAMPS. In addition, the GLP-1-evoked Ca(2+) rise was initiated at the local intercellular peripheral cytoplasm, and a resultant expansion of the intercellular space was also observed. Caffeine induced Ca(2+) elevation in the medium with or without Ca(2+), an effect inhibited by ruthenium red. GLP-1-evoked Ca(2+) oscillations were also enhanced by IBMX, and eliminated by Rp-8-Br-cAMPS or 20 microM H-89 treatments whereas they were unaffected by 2 microM H-89 treatment. Forskolin caused a transient elevation in Ca(2+) that was reduced by Rp-8-Br-cAMPS, 2 microM or 20 microM H-89. Our results indicate that GLP-1 initially generated a local Ca(2+) elevation at the peripheral cytoplasm, subsequently producing Ca(2+) oscillations that were inhibited by ruthenium red, involving ryanodine-sensitive and cAMP-activated CICR mechanisms. The cytoplasmic levels of cAMP as well as local Ca(2+) might be responsible for Ca(2+) oscillations.