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Summary: Activity-dependent gene expression triggered by Ca2+ entry into neurons is critical for learning and memory, but whether specific sources of Ca2+ act distinctly or merely supply Ca2+ to a common pool remains uncertain. Here, we report that both signaling modes coexist and pertain to CaV1 and CaV2 channels, respectively, coupling membrane depolarization to CREB phosphorylation and gene expression. CaV1 channels are advantaged in their voltage-dependent gating and use nanodomain Ca2+ to drive local CaMKII aggregation and trigger communication with the nucleus. In contrast, CaV2 channels must elevate [Ca2+] i microns away and promote CaMKII aggregation at CaV1 channels. Consequently, CaV2 channels are ∼10-fold less effective in signaling to the nucleus than are CaV1 channels for the same bulk [Ca2+] i increase. Furthermore, CaV2-mediated Ca2+ rises are preferentially curbed by uptake into the endoplasmic reticulum and mitochondria. This source-biased buffering limits the spatial spread of Ca2+, further attenuating CaV2-mediated gene expression. [ABSTRACT FROM AUTHOR]

Prolonged AMPA-receptor blockade in hippocampal neuron cultures leads to both an increased expression of GluA1 postsynaptically and an increase in vesicle pool size and turnover rate presynaptically, adaptive changes that extend beyond simple synaptic scaling. As a molecular correlate, expression of the β Ca2+/CaM-dependent kinase type II (βCaMKII) is increased in response to synaptic inactivity. Here we set out to clarify the role of βCaMKII in the various manifestations of adaptation. Knockdown of βCaMKll by lentiviral-mediated expression of shRNA prevented the synaptic inactivity-induced increase in GluA1, as did treatment with the CaM kinase inhibitor KN-93, but not the in- active analog KN-92. These results demonstrate that, spurred by AMPA-receptor blockade, up-regulation of βCaMKII promotes increased GluA1 expression. Indeed, transfection of βCaMKII, but not a kinase-dead mutant increased GluA1 expression on dendrites and elevated vesicle turnover (Syt-Ab uptake), mimicking the effect of synaptic inactivity on both sides of the synapse. In cells with elevated βCaMKll, relief of synaptic-activity blockade uncovered an increase in the frequency of miniature excitatory postsynaptic currents that could be rapidly and fully suppressed by PhTx blockade of GluA1 receptors. This increased mini frequency involved a genuine presynaptic enhancement not merely an increased abundance of synapses. This finding suggests that Ca2+ flux through GluA1 receptors may trigger the acute release of a retrograde messenger. Taken together, our results indicate that synaptic inactivity-induced increases in βCaMKII expression set in motion a series of events that culminate in coordinated pre- and postsynaptic adaptations in synaptic transmission. [ABSTRACT FROM AUTHOR]

Presents information on a study which evaluated the hypothesis that calcitonin gene-related peptide (CGRP) regulates the expression of neurokinin 1 (NK1) receptors via a pathway involving the activation of the transcription factor cAMP response element binding protein (CREB). Measurement of cAMP; Link between CGRP receptor activation and gene expression dependent on activation of CREB protein; Effect of CGRP on NK1 receptor expression.

Tight regulation of calcium entry through the L-type calcium channel CaV1.2 ensures optimal excitation-response coupling. In this issue of Neuron, Michailidis et al. (2014) demonstrate that CaV1.2 activity triggers negative feedback regulation through proteolytic cleavage of the channel within the core of the pore-forming subunit. [Copyright &y& Elsevier]

Prolonged AMPA-receptor blockade in hippocampal neuron cultures leads to both an increased expression of GluA1 postsynaptically and an increase in vesicle pool size and turnover rate presynaptically, adaptive changes that extend beyond simple synaptic scaling. As a molecular correlate, expression of the β Ca(2+)/CaM-dependent kinase type II (βCaMKII) is increased in response to synaptic inactivity. Here we set out to clarify the role of βCaMKII in the various manifestations of adaptation. Knockdown of βCaMKII by lentiviral-mediated expression of shRNA prevented the synaptic inactivity-induced increase in GluA1, as did treatment with the CaM kinase inhibitor KN-93, but not the inactive analog KN-92. These results demonstrate that, spurred by AMPA-receptor blockade, up-regulation of βCaMKII promotes increased GluA1 expression. Indeed, transfection of βCaMKII, but not a kinase-dead mutant, increased GluA1 expression on dendrites and elevated vesicle turnover (Syt-Ab uptake), mimicking the effect of synaptic inactivity on both sides of the synapse. In cells with elevated βCaMKII, relief of synaptic-activity blockade uncovered an increase in the frequency of miniature excitatory postsynaptic currents that could be rapidly and fully suppressed by PhTx blockade of GluA1 receptors. This increased mini frequency involved a genuine presynaptic enhancement, not merely an increased abundance of synapses. This finding suggests that Ca(2+) flux through GluA1 receptors may trigger the acute release of a retrograde messenger. Taken together, our results indicate that synaptic inactivity-induced increases in βCaMKII expression set in motion a series of events that culminate in coordinated pre- and postsynaptic adaptations in synaptic transmission.