Editors' ChoiceNeuroscience

Calmodulin and Brain Development

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Science Signaling  09 Nov 2010:
Vol. 3, Issue 147, pp. ec343
DOI: 10.1126/scisignal.3147ec343

The calcium sensor calmodulin has multiple roles in neurons that include signaling through calmodulin-dependent kinases, regulation of ion channels, and others. Somewhat by accident, investigators have now shown that it appears to function in gene regulation that influences synapse formation and brain development. Pang et al. wanted to test for a potential role of calmodulin as the unidentified high-affinity calcium sensor that allows so-called “asynchronous” neurotransmitter release during intervals in between action potentials. They therefore investigated cortical neurons from knockout mice lacking the calcium-binding protein synaptotagmin-1, which do not show synchronous release of neurotransmitter. This was intended to allow Pang et al. to more easily evaluate effects of shRNA-mediated depletion of calmodulin isoforms on asynchronous release. Instead, they found that such depletion of CaM had no effect on asynchronous release; rather, it restored synchronous neurotransmitter release. Gene expression profiling experiments revealed that expression of about 250 genes was affected by the loss of calmodulin, and amongst those were genes whose products influence neurotransmitter release, including the synaptotagmin-2 gene. The authors noted that loss of calmodulin selectively increased expression of genes like synaptotagmin-2 that are normally preferentially expressed in the hindbrain. Further quantitation of gene expression showed that calmodulin itself was more abundantly expressed in the forebrain, where expression of synaptotagmin-2 is normally repressed. The authors thus propose that calmodulin has a role in brain development and specification of synaptic properties that vary between the forebrain and hindbrain.

Z. P. Pang, W. Xu, P. Cao, T. C. Südhof, Calmodulin suppresses synaptotagmin-2 transcription in cortical neurons. J. Biol. Chem. 285, 33930–33939 (2010). [Abstract] [Full Text]

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