title: Calmodulin priming: nuclear translocation of a calmodulin complex and the memory of prior neuronal activity.
abstract: The neuronal nucleus plays a vital role in information processing, but whether it supports computational functions such as paired-pulse facilitation, comparable to synapses, is unclear. Ca(2+)-dependent movement of calmodulin (CaM) to the nucleus is highly responsive to Ca(2+) entry through L-type channels and promotes activation of the transcription factor CREB (cAMP-responsive element binding protein) through phosphorylation by CaM-sensitive kinases. We characterized key features of this CaM translocation and its possible role in facilitation of nuclear signaling. Nuclear CaM was elevated within 15 s of stimulus onset, preceding the first signs of CREB phosphorylation in hippocampal pyramidal neurons. Depolarization-induced elevation of nuclear CaM also was observed in cerebellar granule cells, neocortical neurons, and dentate gyrus granule cells. Nuclear translocation of CaM was not blocked by disruption of actin filaments or microtubules, or by emptying endoplasmic reticulum Ca(2+) stores with thapsigargin. Translocation of fluorescently tagged CaM was prevented by fusing it with the Ca(2+)/CaM binding peptide M13, suggesting that nuclear CaM accumulation depends on association with endogenous Ca(2+)/CaM binding proteins. To determine whether increased nuclear [CaM] might influence subsequent nuclear signal processing, we compared responses to two consecutive depolarizing stimuli. After a weak "priming" stimulus that caused CaM translocation, CREB phosphorylation caused by a subsequent stimulus was significantly faster, more sensitive to Ca(2+) elevation, and less specifically dependent on Ca(2+) influx through L-type channels. CaM translocation not only supports rapid signaling to the nucleus, but also could provide a "memory" for facilitatory effects of repeated neural activity, seen in altered phosphorylated CREB dynamics and Ca(2+) channel dependence.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: P G
authors.initials: PG
authors.lastname: Mermelstein
authors.forename: K
authors.initials: K
authors.lastname: Deisseroth
authors.forename: N
authors.initials: N
authors.lastname: Dasgupta
authors.forename: A L
authors.initials: AL
authors.lastname: Isaksen
authors.forename: R W
authors.initials: RW
authors.lastname: Tsien
mesh_terms: D000818:Animals; D002147:Calmodulin / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats
chemical_list: D002147:Calmodulin; D017362:Cyclic AMP Response Element-Binding Protein