Molecular mechanisms for generation and interpretation of Ca²⁺ oscillations

Abstract

Ca²⁺ signal is an extremely versatile intracellular regulator controlling various important cell functions such as contraction, secretion, immune responses and synaptic plasticity. The basis for the versatility has been attributed to the capability of Ca²⁺ signals to generate huge variations of spatiotemporal signalling patterns including Ca²⁺ oscillations. However, it remains elusive how Ca²⁺ oscillations are generated and how they are interpreted. We made two approaches to gain an insight into this problem. First, we studied the role of feedback regulation of the inositol 1,4,5-trisphosphate receptor (IP₃R) in Ca²⁺ oscillations. IP₃R is sensitive not only to IP₃ but also to the cytosolic Ca²⁺ concentration. We identified the Ca²⁺ sensor region of the IP₃R through mutagenesis experiments. Ca²⁺ oscillations was inhibited in cells expressing a mutant IP₃R with a decreased Ca²⁺ sensitivity. Therefore, Ca²⁺-mediated feedback regulation of IP₃R is essential for the generation of Ca²⁺ oscillations. We next studied the molecular mechanism that decodes the Ca²⁺ oscillations. For this purpose we used the nuclear factor of active T cells (NFAT), which is known to drive Ca²⁺ oscillation frequency-dependent transcription. Our results showed that NFAT functions as a working memory of Ca²⁺ signals thereby decoding the Ca²⁺ oscillation frequency and regulating its nuclear localization. We also showed that Ca²⁺ oscillation is a cost-effective way to control Ca²⁺-dependent cell functions. These studies provide an insight into the molecular mechanisms for generation and interpretation of Ca²⁺ oscillations. [Jpn J Physiol 54 Suppl:S38 (2004)]