Calcium Signaling to the Nucleus

Activity-dependent transcription in response to neuronal depolarization is necessary for establishment of the long-term plasticity changes underlying learning and memory, such as long-term potentiation (LTP). Neuronal depolarization-dependent calcium (Ca2+) influx initiates signaling cascades responsible for the activation of transcription factors including the nuclear factor of activated T-lymphocytes (NFAT), the cyclic adenosine monophosphate/Ca2+ response element binding protein (CREB), and myocyte enhancer factor 2 (MEF2). While these proteins have been known to play important roles in excitation–transcription (E-T) coupling for decades, recent studies have led to better understanding of their mechanisms of activation and the gene products they control. Specifically, in recent years novel experimental techniques have facilitated understanding of micro and nanodomain organization of Ca2+ signaling pathways around specific Ca2+ sources that couple to activation of NFAT, CREB, and MEF2. Here we review these three Ca2+-dependent transcription factors, their mechanisms of activation, and how the methodologies used to understand one factor may be useful in furthering our understanding of the others. NFAT has recently been shown to be regulated in response to calcineurin (CaN) phosphatase activation downstream of somatic Ca2+ influx through L-type voltage-gated Ca2+ channels (LTCCs) that is triggered by Ca2+ spike propagation from distal dendrites; however, the genes NFAT regulates in response to neuronal activity remain poorly understood. CREB has been well characterized to regulate genes such as c-Fos, Bdnf, and Arc, all of which are necessary for learning and memory, but there are numerous seemingly contradictory proposed mechanisms of CREB activation, most of which propose local kinase signaling around Ca2+ source nanodomains such as N-methyl-D-aspartate (NMDA)-type glutamate receptors (NMDARs) or LTCCs, but that could be preferentially engaged either in dendrites or the soma. In addition, it remains to be seen if these different CREB activation pathways work in tandem or if further studies will demonstrate preferential engagement of one pathway versus another depending on the spatio-temporal characteristics of the upstream stimulus. For MEF2, a number of its downstream gene targets are well characterized, and it is known to be activated downstream of both CaN and kinase signaling pathways, but it is arguably the least well understood in terms of the spatio-temporal Ca2+ signaling dynamics controlling its activation.