Control of cardiac growth and function by calcineurin signaling.

The central role of calcium in the control of cardiac function is well established. The release and reuptake of calcium by the sarcoplasmic reticulum (SR) controls not only the contraction of the cardiac myocyte but, ultimately, the heartbeat. However, the role of calcium as a key second messenger in signal transduction pathways that control growth of the heart has only recently been recognized. The calcium-dependent protein phosphatase calcineurin, also called protein phosphatase 2B, is a critical transducer of calcium signals that govern cardiac growth during development and disease. The actions of calcineurin are dependent on an array of effector proteins that influence its enzymatic activity, subcellular distribution, and stability. Additional proteins transmit calcineurindependent signals to the nucleus with consequent changes in gene transcription. Calcineurin signaling affects the functions of a wide range of cell types and although many of its effectors are ubiquitous, others are restricted to cardiac (and skeletal) muscle, providing muscle specificity to calcineurin signaling. The diversity of calcineurin effectors provides entry points into the signaling pathways that govern cardiac growth and function and provides opportunities for pharmacological and genetic modification of these processes. Here we discuss the functions of calcineurin and its effectors, the possibilities and pitfalls involved in its modulation as a therapeutic target in the heart, and questions for the future.