Modulation of Ca sub(V)2.1 channels by Ca super(2+)/calmodulin-dependent protein kinase II bound to the C-terminal domain

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 1; pp. 341 - 346
• Main Authors: Jiang, Xin, Lautermilch, Nathan J, Watari, Hirofumi, Westenbroek, Ruth E, Scheuer, Todd, Catterall, William A
• Format: Journal Article
• Language: English
• Published: 08-01-2008
• ISSN: 0027-8424; 1091-6490

Ca super(2+)/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 sub(V))2.1 channels that conduct P/Q type Ca super(2+) 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 Ca super(2+)-dependent facilitation of Ca sub(V)2.1 channels. The modulatory effects of CaMKII are reduced by a peptide that prevents binding to Ca sub(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 sub(V)2.1 channels and CaMKII that regulates P/Q-type Ca super(2+) current in neurons. We propose an "effector checkpoint" model for the control of Ca super(2+) channel fitness for function that depends on association with CaMKII, SNARE proteins, and other effectors of Ca super(2+) signals. This regulatory mechanism would be important in presynaptic nerve terminals, where Ca sub(V)2.1 channels initiate synaptic transmission and CaMKII has noncatalytic effects on presynaptic plasticity.