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

What can we make of the apparently diverse group of channels whose activity is regulated by calcium, acting via calmodulin? An important feature common to all of these examples is that calcium feeds back to limit its own entry into the cell (Figure 2Figure 2). In the case of the L-type voltage-dependent calcium channels, the NMDA receptor/channels, and the CNG channels that are permeant to calcium, this negative feedback is an obvious consequence of channel inactivation (Figure 2Figure 2, left). It is also widely believed that at least some calcium-activated potassium channels are located in close proximity to voltage-dependent calcium channels, and so can act directly as sensors of the calcium that flows in through the latter channels. Because potassium channel activation will lead to membrane hyperpolarization and the closing of voltage-dependent calcium channels, calcium-activated potassium channels can act as feedback regulators of calcium entry (Figure 2Figure 2, right). This occurs, for example, in presynaptic nerve terminals, where it may provide an important mechanism for regulating neurotransmitter release.Figure 2Calmodulin as a Negative Feedback Regulator of Calcium Entry Into CellsAs summarized in this minireview, calmodulin (CaM) can regulate the activity of several different kinds of ion channels. At rest (top), when intracellular calcium ([Ca2+]i) is low and calmodulin is not active, calcium-permeant channels (red) are available for calcium entry and calcium-activated potassium channels (blue) are closed. Hence, calcium entry is enabled. After calcium entry, calmodulin binds calcium and is activated (bottom). As a result, the red calcium-permeant channels are inactivated, and the blue calcium-activated potassium channels are open and can hyperpolarize the cell and thereby oppose voltage-dependent calcium entry. A common feature of these actions of calmodulin on different ion channels is that it acts as a calcium sensor and limits the amount of calcium that is allowed to enter the cell. ICa, ICNG, and INMDA refer to calcium currents carried through L-type calcium channels, cyclic nucleotide–gated channels, and NMDA receptor/channels, respectively. ISK and IIK refer to potassium currents carried through the small and intermediate conductance calcium-activated potassium channels, respectively. In the case of the ICa, ISK, and IIK channels, calmodulin is tethered constitutively to the channel even at low intracellular calcium, as shown in the top part of the figure.View Large Image | View Hi-Res Image | Download PowerPoint SlideThe curious finding of Brehm and Eckert finally has a molecular explanation, and a simple and satisfying one at that. The explanation is that L-type calcium channels use calmodulin as their calcium sensor, but in an unusual way: each channel has its own personal stash of calmodulin, which can be activated very quickly by the calcium that the channel itself conducts. Interesting problems of course remain; for example, the nature of the calcium-independent constitutive interaction of calmodulin with ion channels and the role of the essential EF hand motif in the L-type calcium channel (Zuhlke and Reuter 1998xZuhlke, R.D. and Reuter, H. Proc. Natl. Acad. Sci. USA. 1998; 95: 3287–3294CrossRef | PubMed | Scopus (148)See all ReferencesZuhlke and Reuter 1998) should be elucidated. It is notable that several other flavors of calcium channels, the so-called R- and P/Q-type channels encoded by α1E and α1A subunits, respectively, also contain IQ-like motifs in their carboxy-terminal domains and bind calmodulin in a calcium-dependent manner (Peterson et al. 1999xPeterson, B.Z., DeMaria, C.D., and Yue, D.T. Neuron. 1999; 22: 549–558Abstract | Full Text | Full Text PDF | PubMedSee all ReferencesPeterson et al. 1999). These channels do not exhibit calcium-dependent inactivation, but certainly it is conceivable that some other key channel property is regulated by calcium/calmodulin. I very much doubt that we have seen the last of calmodulin as a modulator of membrane ion channels.*E-mail: levitan@brandeis.edu.