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

Department of Molecular and Cellular Physiology, Beckman Center for Molecular and Genetic Medicine, Stanford University School of Medicine, California 94305-5426, USA.
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.

19 Reads
  • Source
    • "(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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Synaptic plasticity requires transcription and translation to establish long-term changes that form the basis for long term memory. Diverse stimuli, such as synaptic activity and growth factors, trigger synthesis of mRNA to regulate changes at the synapse. The palette of possible mRNAs is vast, and a key question is how the cell selects which mRNAs to synthesize. To address this molecular decision-making, we have developed a biochemically detailed model of synaptic-activity triggered mRNA synthesis. We find that there are distinct time-courses and amplitudes of different branches of the mRNA regulatory signaling pathways, which carry out pattern-selective combinatorial decoding of stimulus patterns into distinct mRNA subtypes. Distinct, simultaneously arriving input patterns that impinge on the transcriptional control network interact nonlinearly to generate novel mRNA combinations. Our model combines major regulatory pathways and their interactions connecting synaptic input to mRNA synthesis. We parameterized and validated the model by incorporating data from multiple published experiments. The model replicates outcomes of knockout experiments. We suggest that the pattern-selectivity mechanisms analyzed in this model may act in many cell types to confer the capability to decode temporal patterns into combinatorial mRNA expression.
    PLoS ONE 05/2014; 9(5):e95154. DOI:10.1371/journal.pone.0095154 · 3.23 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Early odor preference training in rat pups produces behavioral preferences that last from hours to lifetimes. Here, we discuss the molecular and circuitry changes we have observed in the olfactory bulb (OB) and in the anterior piriform cortex (aPC) following odor training. For normal preference learning, both structures are necessary, but learned behavior can be initiated by initiating local circuit change in either structure. Our evidence relates dynamic molecular and circuit changes to memory duration and storage localization. Results using this developmental model are consistent with biological memory theories implicating N-methyl-D-aspartate (NMDA) receptors and β-adrenoceptors, and their associated cascades, in memory induction and consolidation. Finally, our examination of the odor preference model reveals a primary role for increases in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor synaptic strength, and in network strength, in the creation and maintenance of preference memory in both olfactory structures.
    Progress in brain research 04/2014; 208:115-56. DOI:10.1016/B978-0-444-63350-7.00005-X · 2.83 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Activation of the growth hormone (GH) secretagogue receptor (GHS-R) by synthetic GH releasing peptides (GHRP) or its endogenous ligand (Ghrelin) stimulates GH release. Though much is known about the signal transduction underlying short-term regulation, there is far less information on the mechanisms that produce long-term effects. In the current report, using an enzyme-linked immunosorbent assay for GH detection and whole-cell patch-clamp recordings, we assessed the long-term actions of such regulatory factors on voltage-activated Ca(2+) currents in bovine somatotropes (BS) separated on a Percoll gradient and detected by immunohistochemistry. After 24 h of treatment with Ghrelin (10 nM) or GHRP-6 (100 nM) enhanced BS secretory activity; GH secretion stimulated by GHS through the activation of GHS-R because treatment with the antagonist of GHS-R (D-Lys3-GHRP-6, 10 μM) blocked the GH secretion, and the effect was dose and time dependent (24, 48, and 72 h). GH secretion stimulated by GHRP-6 was abolished by nifedipine (0.5 μM), a blocker of L-type HVA Ca(2+) channels, and KN-62 (10 μM), an inhibitor of Ca(2+)/CaM-KII. After 72 h in culture, all recorded BS exhibited two main Ca(2+) currents: a low voltage-activated (LVA; T-type) and a high voltage-activated (HVA; mostly dihydropyridine-sensitive L-type) current. Interestingly, HVA and LVA channels were differentially upregulated by Ghrelin. Chronic treatment with the GHS induced a significant selective increase on the Ba(2+) current through HVA Ca(2+) channels, and caused only a small increase of currents through LVA channels. The stimulatory effect on HVA current density was accompanied by an augment in maximal conductance with no apparent changes in the kinetics and the voltage dependence of the Ca(2+) currents, suggesting an increase in the number of functional channels in the cell membrane. Lastly, in consistency with the functional data, quantitative real-time RT-PCR revealed transcripts encoding for the Cav1.2 and Cav1.3 pore-forming subunits of L-type channels. The treatment with Ghrelin significantly increased the Cav1.3 subunit expression, suggeting that the chronic stimulation of the GHS receptor with Ghrelin or GHRP-6 increases the number of voltage-gated Ca(2+) channels at the cell surface of BS.
    12/2013; 2013(26):527253. DOI:10.1155/2013/527253
Show more


19 Reads
Available from