Haruhiko Bito

CREB Phosphorylation and Dephosphorylation: A Ca2+- and Stimulus Duration–Dependent Switch for Hippocampal Gene Expression

While changes in gene expression are critical for many brain functions, including long-term memory, little is known about the cellular processes that mediate stimulus-transcription coupling at central synapses. In studying the signaling pathways by which synaptic inputs control the phosphorylation state of cyclic AMP-responsive element binding protein (CREB) and determine expression of CRE-regulated genes, we found two important Ca2+/calmodulin (CaM)-regulated mechanisms in hippocampal neurons: a CaM kinase cascade involving nuclear CaMKIV and a calcineurin-dependent regulation of nuclear protein phosphatase 1 activity. Prolongation of the synaptic input on the time scale of minutes, in part by an activity-induced inactivation of calcineurin, greatly extends the period over which phospho-CREB levels are elevated, thus affecting induction of downstream genes.

Signaling from Synapse to Nucleus: Postsynaptic CREB Phosphorylation during Multiple Forms of Hippocampal Synaptic Plasticity

Phosphorylation of the transcription factor CREB is thought to be important in processes underlying long-term memory. It is unclear whether CREB phosphorylation can carry information about the sign of changes in synaptic strength, whether CREB pathways are equally activated in neurons receiving or providing synaptic input, or how synapse-to-nucleus communication is mediated. We found that Ca(2+)-dependent nuclear CREB phosphorylation was rapidly evoked by synaptic stimuli including, but not limited to, those that induced potentiation and depression of synaptic strength. In striking contrast, high frequency action potential firing alone failed to trigger CREB phosphorylation. Activation of a submembranous Ca2+ sensor, just beneath sites of Ca2+ entry, appears critical for triggering nuclear CREB phosphorylation via calmodulin and a Ca2+/calmodulin-dependent protein kinase.

Ca2+-dependent regulation in neuronal gene expression

Ca2+ is an important signal-transduction molecule that plays a role in many intracellular signaling pathways. Recent advances have indicated that in neurons, Ca2+-controlled signaling mechanisms cooperate in order to discriminate amongst incoming cellular inputs. Ca2+-dependent transcriptional events can thereby be made selectively responsive to bursts of synaptic activity of specific intensity or duration.

Dendritic Ca2+ Channels Characterized by Recordings from Isolated Hippocampal Dendritic Segments

Dendritic arbors are critical for the information processing capability of central neurons, but quantitative analysis of their membrane properties has been hampered by their geometrical complexity. Here, we have focused on an important source of Ca2+ entry in dendrites, the voltage-gated Ca2+ channels, by applying the whole-cell voltage-clamp technique to isolated dendritic segments (dendrosomes) from rat hippocampal neurons. We found that low voltage-activated T-type Ca2+ channels provide a significantly larger fraction of the Ca2+ influx in dendrites than their counterparts in cell bodies. Surprisingly, 60%-70% of the high voltage-activated Ca2+ current in dendrosomes was N and P/Q type, and these channels were susceptible to neurotransmitter inhibition, suggesting a novel physiological role for G protein-regulated Ca2+ channel modulation in controlling dendritic excitability and Ca2+ signaling.

Synaptic Plasticity: A molecular mechanism for metaplasticity

Abstract The results of expressing a constitutive form of a prominent synaptic kinase in transgenic mice suggest how there can be a sliding threshold for synapse modification, an important element in some learning theories.

Molecular Characterization and Physiological Functions of PAF Receptors

Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphoryl-choline) is an alkylether phospholipid that possesses a wide range of biological effects in many physiological and pathological responses such as platelet aggregation, neutrophil chemotaxis, macrophage activation, blood pressure regulation, or smooth muscle contraction (1–7). PAF was also recently shown to be a potentially important signaling molecule in neuronal signal transduction (8–11). While the Ca2+-dependent synthesis and catabolism of PAF still remain to be fully characterized, converging lines of evidence suggested the existence of a specific surface receptor for PAF in diverse systems (5–7). Recent molecular cloning of PAF receptors from various species (12–16) has enabled to obtain further insights in the diverse biological functions and signaling mechanisms mediated through this receptor. In this proceeding, we will focus on the molecular structure of PAF receptor, its gene regulation and its multiple signal transduction pathways.