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Gating of long‐term depression by Ca 2+ /calmodulin‐dependent protein kinase II through enhanced cGMP signalling in cerebellar Purkinje cells
Author(s) -
Kawaguchi Shinya,
Hirano Tomoo
Publication year - 2013
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2012.245787
Subject(s) - protein kinase a , microbiology and biotechnology , cgmp dependent protein kinase , calmodulin , kinase , purkinje cell , long term depression , chemistry , gating , neuroscience , cerebellum , biology , biochemistry , mitogen activated protein kinase kinase , glutamate receptor , receptor , ampa receptor , enzyme
Key points• Long‐term depression (LTD) at parallel fibre synapses on a cerebellar Purkinje cell has been regarded as a cellular basis for motor learning. • Although Ca 2+ /calmodulin‐dependent protein kinase II (CaMKII) has been implicated in the LTD induction and motor learning, the underlying molecular mechanism remains unclear. • By combined application of simulation and experiments, we have attempted to explore the potential signalling pathway underlying the CaMKII involvement in LTD. Our data show that CaMKII supports the LTD‐inducing signalling pathway consisting of other protein kinases such as protein kinase C and mitogen‐activated protein kinase. • The gating of the LTD‐inducing pathway by CaMKII is mediated by negative regulation of phosphodiesterase 1, and the resultant facilitation of the cGMP/protein kinase G (PKG) pathway. As a result, protein phosphatase 2A activity was suppressed, supporting the LTD induction. • In addition, nitric oxide‐mediated cGMP/PKG activation compensated for the lack of CaMKII activation in LTD induction. • This study provides a comprehensive understanding of elaborate intracellular signalling mechanisms for LTD regulation.Abstract Long‐term depression (LTD) at parallel fibre synapses on a cerebellar Purkinje cell has been regarded as a cellular basis for motor learning. Although Ca 2+ /calmodulin‐dependent protein kinase II (CaMKII) has been implicated in the LTD induction as an important Ca 2+ ‐sensing molecule, the underlying signalling mechanism remains unclear. Here, we attempted to explore the potential signalling pathway underlying the CaMKII involvement in LTD using a systems biology approach, combined with validation by electrophysiological and FRET imaging experiments on a rat cultured Purkinje cell. Model simulation predicted the following cascade as a candidate mechanism for the CaMKII contribution to LTD: CaMKII negatively regulates phosphodiesterase 1 (PDE1), subsequently facilitates the cGMP/protein kinase G (PKG) signalling pathway and down‐regulates protein phosphatase 2A (PP‐2A), thus supporting the LTD‐inducing positive feedback loop consisting of mutual activation of protein kinase C (PKC) and mitogen‐activated protein kinase (MAPK). This model suggestion was corroborated by whole‐cell patch clamp recording experiments. In addition, FRET measurement of intracellular cGMP concentration revealed that CaMKII activation causes sustained increase of cGMP, supporting the signalling mechanism of LTD induction by CaMKII. Furthermore, we found that activation of the cGMP/PKG pathway by nitric oxide (NO) can support LTD induction without activation of CaMKII. Thus, this study clarified interaction between NO and Ca 2+ /CaMKII, two important factors required for LTD.