Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 1, Pages 341-346Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0710213105
Keywords
calcium channels; facilitation; phosphorylation; synaptic transmission
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Funding
- NINDS NIH HHS [R01 NS022625, R01 NS22625] Funding Source: Medline
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Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a key regulator of synaptic responses in the postsynaptic density, but understanding of its mechanisms of action in the presynaptic neuron is incomplete. Here we show that CaMKII constitutively associates with and modulates voltage-gated calcium (Ca-v)2.1 channels that conduct P/Q type Ca2+ currents and initiate transmitter release. Both exogenous and brain-specific inhibitors of CaMKII accelerate voltage-dependent inactivation, cause a negative shift in the voltage dependence of inactivation, and reduce Ca2+-dependent facilitation of Ca(v)2.11 channels. The modulatory effects of CaMKII are reduced by a peptide that prevents binding to Ca(v)2.1 channels but not by a peptide that blocks catalytic activity, suggesting that binding rather than phosphorylation is responsible for modulation. Our results reveal a signaling complex formed by Ca(v)2.1 channels and CaMKII that regulates P/Q-type Ca2+ current in neurons. We propose an '' effector checkpoint '' model for the control of Ca2+ channel fitness for function that depends on association with CaMKII, SNARE proteins, and other effectors of Ca2+ signals. This regulatory mechanism would be important in presynaptic nerve terminals, where Ca(v)2.1 channels initiate synaptic transmission and CaMKII has noncatalytic effects on presynaptic plasticity.
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