The Calcium Sensor for Slow Afterhyperpolarization

Abstract

Neurons in the brain protect themselves from excessive activity in part by a mechanism through which an influx of calcium ions activates potassium channels, which then cause hyperpolarization of the nerve cell, thus inhibiting further action potentials. The identity of this potassium channel is not known, but the current it conducts is called the slow afterhyperpolarization current (I sAHP ). Tzingounis et al . identified a new key component of the mechanism by which calcium influences the channel: the neuronal calcium sensor family member known as hippocalcin. The authors interpreted results from kinetic analysis of I sAHP in the presence of various calcium buffers to indicate that I sAHP responded primarily to general changes in calcium concentration within the cell, as opposed to large rapid changes in calcium concentration in the immediate vicinity of calcium channels. The latter is characteristic of other potassium channels that exist together with calcium channels in large complexes in which the calcium sensor is bound to or part of the potassium channel. Instead, the sAHP channels appeared to be regulated by a diffusible calcium sensor, so the authors suspected hippocalcin. They found that, indeed, hippocampal slices from hippocalcin knockout mice lacked I sAHP , whereas expression of hippocalcin in cultured neurons enhanced I sAHP . Hippocalcin contains a "myristoyl switch," a mechanism by which a conformational change induced by calcium binding causes exposure of a myristoyl moiety that causes hippocalcin to bind to the plasma membrane. A mutant lacking the myristoylation site failed to increase I sAHP . The authors therefore propose that hippocalcin senses global changes in the concentration of intracellular free calcium and relays that information back to the plasma membrane. Brown et al . point out in commentary that elucidation of the mechanism by which hippocalcin actually regulates the sAHP channel, be it direct or through another messenger molecule (hippocalcin is known to bind phosphatidylinositol 4,5-bisphosphate), may be possible only when the so-far-elusive molecular identity of the sAHP channel itself is resolved. A. V. Tzingounis, M. Kobayashi, K. Takamatsu, R. A. Nicoll, Hippocalcin gates the calcium activation of the slow afterhyperpolarization in hippocampal pyramidal cells. Neuron 53 , 487-493 (2007). [Online Journal] D. A. Brown, B. Lancaster, M. M. Shah, Hippocalcin: A new solution to an old puzzle. Neuron 53 , 467-468 (2007). [Online Journal]