It Is Calmodulin After All! Mediator of the Calcium Modulation of Multiple Ion Channels

نویسنده

  • Irwin B. Levitan
چکیده

this concept. In fact, channelologists have had this idea for some time, but a rather general experimental finding has been that standard calmodulin inhibitors that block the calcium-dependent binding of calmodulin to its target proteins do not interfere with calcium regulation of ion channels. Ching Kung and his colleagues proposed more than a decade ago (reviewed by Saimi and Kung, 1994) that calmodulin might mediate the activation of Just over 20 years ago, Paul Brehm and the late Roger calcium-activated potassium (and calcium-activated sodi-Eckert reported a curious finding in a curious organism: um) channels in Paramecium, but until recently there voltage-dependent calcium channels in the ciliate Para-was no indication that this is the case other than in this mecium are not only opened by membrane depolariza-curious organism. tion, they also are inactivated during a sustained depo-Calcium-activated potassium channels, which use larization, by the very calcium that enters through the potassium as their charge carrier but require intracellular open calcium channels (Brehm and Eckert, 1978) (see calcium to help them open, also come in several flavors. Figure 1). This kind of calcium-dependent inactivation One of these is a relatively small conductance channel, was very different from the time-and voltage-dependent the SK channel, that is responsible for the slow afterhy-inactivation of axonal sodium channels that had been perpolarization that follows an action potential and described a generation earlier by Hodgkin and Huxley. thereby regulates the frequency of action potential firing Thus, their initial report was greeted with a touch of in neurons. John Adelman and his colleagues (Xia et al., skepticism, but Eckert and his colleagues soon put all 1998) used a yeast two-hybrid assay and biochemical doubts to rest with a series of lovely papers confirming techniques to show that calmodulin binds constitutively the essential role of calcium in the inactivation process, to this channel, even in the absence of calcium. This and extending the finding to neurons as well (e.g., Eckert is reminiscent of the enzyme phosphorylase kinase, of and Tillotson, 1981). which calmodulin is an obligatory subunit that can be With the demonstration that calcium channels come removed only under denaturing conditions (Picton et al., in multiple flavors with different properties, and the sub-1980). The coexpression of the SK channel with mutant sequent cloning of cDNAs encoding the pore-forming calmodulins that exhibit altered affinity for calcium subunits for many of these channel types (see Catterall, changes the calcium sensitivity …

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عنوان ژورنال:
  • Neuron

دوره 22  شماره 

صفحات  -

تاریخ انتشار 1999