Calmodulin binding proteins provide domains of local Ca2+ signaling in cardiac myocytes

Calmodulin (CaM) acts as a common Ca2+ sensor for many signaling pathways, transducing local Ca2+ signals into specific cellular outcomes. Many of CaM's signaling functions can be explained by its unique biochemical properties, including high and low affinity Ca2+-binding sites with slow and fast kinetics, respectively. CaM is expected to have a limited spatial range of action, emphasizing its role in local Ca2+ signaling. Interactions with target proteins further fine-tune CaM signal transduction. Here, we focus on only three specific cellular targets for CaM signaling in cardiac myocytes: the L-type Ca2+ channel, the ryanodine receptor, and the IP3 receptor. We elaborate a working hypothesis that each channel is regulated by two distinct functional populations of CaM: dedicated CaM and promiscuous CaM. Dedicated CaM is typically tethered to each channel and directly regulates channel activity. In addition, a local pool of promiscuous CaM appears poised to sense local Ca2+ signals and trigger downstream pathways such as Ca2+/CaM dependent-protein kinase II and calcineurin. Understanding how promiscuous CaM coordinates multiple distinct signaling pathways remains a challenge, but is aided by the use of mathematical modeling and a new generation of fluorescent biosensors. This article is part of a special issue entitled Local Signaling in Myocytes. (C) 2011 Elsevier Ltd. All rights reserved.