In the brain, calcium influx following a train of action potentials activates potassium channels that mediate a slow afterhyperpolarization current (IsAHP). The key steps between calcium influx and potassium channel activation remain unknown. Here we report that the key intermediate between calcium and the sAHP channels is the diffusible calcium sensor hippocalcin. Brief depolarizations sufficient to activate the IsAHPin wild-type mice do not elicit the IsAHPin hippocalcin knockout mice. Introduction of hippocalcin in cultured hippocampal neurons leads to a pronounced IsAHP, while neurons expressing a hippocalcin mutant lacking N-terminal myristoylation exhibit a small IsAHPthat is similar to that recorded in uninfected neurons. This implies that hippocalcin must bind to the plasma membrane to mediate its effects. These findings support a model in which the calcium sensor for the sAHP channels is not preassociated with the channel complex. © 2007 Elsevier Inc. All rights reserved.
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