Deisseroth, K., Heist, E. K. & Tsien, R. W. Calmodulin translocation to the nucleus supports CREB phosphorylation in hippocampal neurons. Nature 392, 198-202

Stanford University, Stanford, California, United States
Nature (Impact Factor: 41.46). 03/1998; 392(6672):198-202. DOI: 10.1038/32448
Source: PubMed


Activation of the transcription factor CREB is thought to be important in the formation of long-term memory in several animal species. The phosphorylation of a serine residue at position 133 of CREB is critical for activation of CREB. This phosphorylation is rapid when driven by brief synaptic activity in hippocampal neurons. It is initiated by a highly local, rise in calcium ion concentrations near the cell membrane, but culminates in the activation of a specific calmodulin-dependent kinase known as CaMK IV, which is constitutively present in the neuronal nucleus. It is unclear how the signal is conveyed from the synapse to the nucleus. We show here that brief bursts of activity cause a swift (approximately 1 min) translocation of calmodulin from the cytoplasm to the nucleus, and that this translocation is important for the rapid phosphorylation of CREB. Certain Ca2+ entry systems (L-type Ca2+ channels and NMDA receptors) are able to cause mobilization of calmodulin, whereas others (N- and P/Q-type Ca2+ channels) are not. This translocation of calmodulin provides a form of cellular communication that combines the specificity of local Ca2+ signalling with the ability to produce action at a distance.

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    • "(H) Relative increase in pCREB-CRE in presence of L-LTP (four pulses of 100 Hz for 1 sec after every 5 min) [60]. (I) Time course of pCREB-CRE in presence of 50 Hz for 18 sec [67]. (J) Dose-response for pCREB-CRE with change in CBP [68]. "
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    • "L-type calcium channels (LTCCs), a long-opening high-voltage-gated calcium channel , are known to play an important role in triggering intracellular cascades related to synaptic plasticity (Deisseroth et al., 1998; Mermelstein et al., 2000) and in Hebbian synaptic plasticity at glutamatergic synapses (Bauer et al., 2002; Grover and Teyler, 1990, 1992; Weisskopf et al., 1999). We have investigated the potential contribution of these channels to early odor preference learning (Jerome et al., 2012). "
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    • "Hence, nuclear Ca2+ transients in neurons activate gene transcription by a mechanism that involves the cAMP response element (CRE) and the CRE-binding protein, CREB [43]. In hippocampal neurons, for example, Ca2+ influx through L-type channels (and N-methyl-D-aspartate receptors) is capable of causing rapid translocation of Ca2+/CaM-K II/IV to the nucleus, which is important for CREB phosphorylation [44]. Signaling pathways mediating the major neuroendocrine regulators of mammalian somatotropes reported by Chang et al. [45] include membrane voltage-sensitive ion channels, Na+/H+ antiport, Ca2+ signaling, multiple pharmacologically distinct intracellular Ca2+ stores, cAMP/PKA, PKC, nitric oxide, cGMP, MEK/ERK, and PI3K. "
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