Signaling through calcium, calcineurin, and NF-AT in lymphocyte activation and development.

Abstract

Although the signaling pathway defined by calcium(Ca++), calcineurin, and the NF-ATc family of transcription factors is now known to function in many cell types,it was originally discovered in lymphocytes, and its biologic roles to date are probably best understood in lymphocytes. NF-ATc proteins have an important role in initiating immune responses by responding to antigenreceptor signaling and activating early immune responsegenes, including cell surface molecules, cytokines, andother transcription factors that coordinate the actions of Tcells as well as other cell types. In addition, it now seemsthat this pathway is used in the development of embryonicheart valves, differentiation of slow and fast muscle fibers,responses to synaptic activity in neurons, and cardiomyocyte growth. Many of the molecular steps carrying information from the T-cell receptor to the formation of activeNF-AT transcription complexes are now known (Fig. 1).However, there remain important gaps in our knowledgeof the regulation of signaling through this pathway. Forexample, how is Ca++ regulated upstream of calcineurinand NF-ATc through calcium release-activated calcium(CRAC) channels to produce optimal Ca++ fluxes? Whatis the molecular nature of the CRAC channels that appearto be essential for lymphocyte activation? How does thesignaling pathway discriminate between types of Ca++signals and sources of Ca++? What is the mechanism bywhich calcineurin dephosphorylation of NF-ATc directsnuclear import? How is NF-ATc signaling terminated, andwhat are the roles of kinases that oppose calcineurin's action on NF-ATc? Why is an NF-AT-driven transgene expressed specifically in activated lymphocytes, when theproteins thought to make up the NF-AT transcription complex are widely expressed? Why have NF-ATc proteinsevolved to bind DNA poorly and in cooperation with nuclear partners? However, the most mysterious aspect ofthis pathway (and also others) is how a ubiquitous signaling pathway comes to participate in biologically specificsignaling events. This paper highlights these issues andsuggests avenues of investigation...