Worm Breeder's Gazette 16(3): 28 (June 1, 2000)
These abstracts should not be cited in bibliographies. Material contained herein should be treated as personal communication and should be cited as such only with the consent of the author.
|1||CNS Department, Hoffmann-La Roche, 4070 Basel, Switzerland|
|2||Stanford University School of Medicine, Stanford, California 94305-5125|
Long-term potentiation (LTP) is considered to represent a form of synaptic plasticity that may underlie learning and memory processes. Although the exact biochemical pathways and molecular mechanisms involved are unknown, several lines of evidence suggest that various protein kinases play a role in LTP (1). For example, genetic modifications of the calcium/calmodulin-dependent protein kinase II (CaMKII) have profound effects on LTP that are also reflected by in vivo behavior studies in mice, ranging from alterations in social responses to profound deficits in spatial learning tasks (2,3).
In vertebrates, CaMKII isoforms are encoded by at least four genes (a, b, g, d). Each one gives rise to several isoforms by mode of alternative splicing. However, the domain organization of all the proteins within the CaMKII family is almost identical. The domains are: a N-terminal catalytic domain, a regulatory domain containing the calmodulin (CaM)-binding site and the autophosphorylation site, a variable region and a C-terminal association domain that mediates formation of a large holoenzyme complex composed of 10-12 monomer subunits. Insertion of extra amino acids in any of these domains affects the function of the enzyme and/or alters the assembly of the monomers. CaMKII has been proposed to function in a neuron as a memory switch and as a calcium-spike frequency decoder, mostly through its capability to modulate its enzymatic activity via autophosphorylation.
The unc-43 gene encodes a C. elegans CaMKII orthologue (Ce-CaMKII), and mutations in unc-43 cause multiple behavioral defects in locomotory activity, in the clock control of defecation, regulation of body-wall muscle excitation and spontaneous activity (4). The absence of Ce-CaMKII or expression of either an inactive or a constitutively-activated form of CaMKII in C. elegans fails to localize the AMPA-type glutamate receptor GLR-1 to synaptic sites, suggesting that Ce-CaMKII regulates the density of central glutamatergic synapses in vivo (5).
C. elegans has not yet been used extensively as a model to study the mechanisms of associative learning. Therefore, a better knowledge of the biochemical characteristics and functions of CaMKII in C. elegans may allow us to understand if the molecular mechanisms of associative learning/memory in this organism are CaMKII-dependent. We have cloned and sequenced cDNAs encoding the Ce-CaMKII and found that the unc-43 gene encodes at least seven CaMKII isoforms. We are now characterizing the basic catalytic and structural properties of these seven isoforms and comparing their biochemical activities with mammalian neuronal CaMKII isoenzymes, more specifically the catalytic properties, the autophosphorylation levels, the calcium dependence, and CaM sensitivity as well as the formation of oligomeric holoenzymes.
(1) Jie Liu, Kohji Fukunaga, Hideyuki Yamamoto, Katsuhide Nishi, and Eishichi Miyamoto. Differential Roles of Calcium/Calmodulin-Dependent Protein Kinase II and Mitogen-Activated Protein Kinase Activation in Hippocampal Long-Term Potentiation. The Journal of Neuroscience, 1999, 19(19): 8292-8299.
(2) Alcino J. Sylva, Alan M. Smith, and Karl Peter Giese. Gene Targeting and The Biology of Learning and Memory. Annu. Rev. Genet. 1997. 31:527-46.
(3) Karl Peter Giese, Nikola B. Fedorov, Robert K. Filopkowski, Alsino J. Silva. Autophosphorylation at Thr286 of the a Calcium-Calmodulin Kinase II in LTP and learning. Science, vol. 279, 6 February 1998.
(4) David J. Reiner, Elizabeth M. Newton, Hong Tian & James H. Thomas. Diverse behavioral defects caused by mutations in Caenorhabditis elegans unc-43 CaM Kinase II. Nature. Vol. 402, 11 November 1999.
(5) Christopher Rongo & Joshua M. Kaplan. CaMKII regulates the density of central glutamatergic synapses in vivo. Nature, Vol. 402, 11 November 1999.