KRAS-induced actin-interacting protein regulates inositol 1,4,5-trisphosphate-receptor-mediated calcium release.

KRAS-induced actin-interacting protein (KRAP) was originally characterized as a filamentous- actin-interacting protein. We have recently found that KRAP is an associated molecule with inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R) and is responsible for the proper subcellular localization of IP(3)R. Since it remains unknown whether KRAP regulates the IP(3)R-mediated Ca(2+) signaling, we herein examined the effects of KRAP on the IP(3)R-mediated Ca(2+) release by Ca(2+) imagings in the cultured HEK293 or MCF7 cells. Reduction of KRAP protein by KRAP-specific siRNA diminishes ATP-induced Ca(2+) release and the ATP-induced Ca(2+) release is completely quenched by the pretreatment with the IP(3)R inhibitor but not with the ryanodine receptor inhibitor, indicating that KRAP regulates IP(3)R-mediated Ca(2+) release. To further reveal mechanistic insights into the regulation of IP(3)R-mediated Ca(2+) release by KRAP, we examined the effects of the KRAP-knockdown on the releasable Ca(2+) content of intracellular Ca(2+) stores. Consequently, reduction of KRAP does not affect the amount of ionophore- or Ca(2+)-ATPase inhibitor-induced Ca(2+) release in the HEK293 cells, indicating that releasable Ca(2+) content of intracellular Ca(2+) stores is not altered by KRAP. Thus, KRAP is involved in the proper regulation of IP(3)R-mediated Ca(2+) release.

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