Calcineurin Finds a New Partner in the L-Type Ca 2+ Channel

Abstract

See related articles, pages 51–60 Calcineurin is a Ca2+/calmodulin-sensitive phosphatase that sits near the top of signaling pathways leading to pathological cardiac hypertrophy.1 Pathological stressors activate calcineurin, for which nuclear factor of activated T cells (NFAT) is a principal substrate. Dephosphorylation unmasks a nuclear localization signal on NFAT, which then translocates to the nucleus and, there, serves as part of a transcription factor complex able to initiate gene expression cascades that induce cardiac hypertrophy and subsequent heart failure. Determining how calcineurin is specifically activated in response to hypertrophic stressors by the same Ca2+ signal used for excitation–contraction coupling has been a major challenge. Triggered by Ca2+ influx through CaV1.2 voltage-gated Ca2+ channels at the sarcolemmal membrane, intracellular calcium briefly increases 10-fold with each heart beat to generate myocyte contraction. Almost as quickly, intracellular calcium falls to its baseline level, allowing myocyte relaxation and preparation for the next beat. There are 2 leading proposals for how Ca2+ could activate the calcineurin/NFAT pathway or function as a versatile regulator of multiple other signaling cascades in the face of the large Ca2+ oscillations driving each cycle of contraction and relaxation. One is that modulation of the amplitude and/or frequency of …