Cardiovascular Research

Cardiovascular Research 2007 73(4):641-647; doi:10.1016/j.cardiores.2006.10.019

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Copyright © 2006, European Society of Cardiology

Calmodulin and CaMKII as molecular switches for cardiac ion channels

Geoffrey S. Pitt^*

Department of Medicine, Division of Cardiology, College of Physicians and Surgeons of Columbia University, 630 W 168th St, PH 7W 318, New York, NY 10032, USA
Department of Pharmacology, College of Physicians and Surgeons of Columbia University, 630 W 168th St, PH 7W 318, New York, NY 10032, USA

^* Department of Pharmacology, College of Physicians and Surgeons of Columbia University, 630 W 168th St, PH 7W 318, New York, NY 10032, USA. Tel.: +1 212 305 1009; fax: +1 212 305 8780. Email address: gp2004{at}columbia.edu

Received 18 September 2006; revised 20 October 2006; accepted 25 October 2006

	Abstract

Top Abstract 1. Introduction References

 
Because changes in intracellular Ca²⁺ concentration are the final signals of electrical activity in excitable cells, many mechanisms have evolved to regulate Ca²⁺ influx. Among the most important are those pathways that directly regulate the ion channels responsible for regulating and generating the Ca²⁺ influx signal. Recent work has demonstrated that the Ca²⁺ binding protein calmodulin (CaM) and the Ca²⁺/CaM-sensitive kinase CaMKII are important modulators of cardiac ion channels. Thus, Ca²⁺ participates in feedback modulation to control electrical activity. This review highlights various mechanisms by which CaM and CaMKII regulate cardiovascular ion channel activity and presents a novel model for CaMKII regulation of Ca_V1.2 Ca²⁺ channel function.

KEYWORDS Ion channel; Calcium; Calmodulin; CaMKII; Calcium channel; Sodium channel; Potassium channel; KCNQ1; Subunit assembly

	1. Introduction

Top Abstract 1. Introduction References

 
Virtually every cellular action triggered by electrical activity–e.g., muscle contraction, neurotransmitter release, or hormone secretion–depends upon an increase in the concentration of intracellular Ca²⁺. Since the source of Ca²⁺ is, in general, voltage-gated Ca²⁺ channels, their presence is considered the signature feature of an excitable cell and a simplistic view of other ion channels is that they mainly serve to regulate membrane potential in order to control Ca²⁺ channels. Thus, it is not surprising that a growing body of work has shown that ion channels themselves are among the many targets of intracellular Ca²⁺, providing an important mode of feedback modulation for intracellular Ca²⁺ to control the very gates that regulate its level.

The proteins that translate changes in Ca²⁺ into modulation of ion channel function are a subset of the Ca²⁺ binding proteins that regulate Ca²⁺-signaling pathways in excitable cells. Most studied has been calmodulin (CaM). Highly conserved among eukaryotes, CaM modulates effector proteins through direct binding or indirectly by activation of Ca²⁺/CaM-sensitive kinases or phosphatases. This review will focus on the mechanisms by which CaM and the Ca²⁺/CaM-sensitive kinase CaMKII participate in the feedback modulation of cardiovascular ion channel function.

1.1. Ca²⁺/calmodulin-dependent inactivation of Ca²⁺ channels
Ca²⁺-dependent inactivation (CDI) of Ca²⁺ channels serves as a classical example of Ca²⁺/CaM regulation of ion channel function. Originally reported by Brehm and Eckert [1], CDI denotes the accelerated channel inactivation seen in experiments when Ca²⁺ is used as the charge carrier rather than another permeant divalent cation, such as Ba²⁺. When first discovered, CDI represented an interesting anomaly to models of ion channel function described by Hodgkin and Huxley. In contrast to the voltage-dependent inactivation of Na⁺ or K⁺ channels, CDI described a process in which the permeant ion influenced channel function and thereby provided a means of controlling Ca²⁺ influx at the point of Ca²⁺ entry. CDI is a major determinant of the duration of the cardiac action potential. Perturbation of CDI disturbs the tight balance between Ca²⁺ influx through Ca_V1.2 L-type Ca²⁺ channels and K⁺ efflux through the multiple K⁺ channels that defines the plateau phase of the cardiac action potential and thereby leads to action potential prolongation [2].

The recent discovery of the molecular details of CDI has provided the framework for exploring Ca²⁺ regulation of other ion channels. Two specific insights stand out: it was shown that a region within the C terminus (CT) of the pore-forming _1C subunit of Ca_V1.2 contained an "IQ" motif [3], a consensus binding motif for CaM; and the Ca²⁺ sensor for CDI was, indeed, CaM [4,5]. Leading to those studies was the demonstration that the site of action for Ca²⁺ resided within the CT of _1C and then mutagenesis that defined a short region in the _1C CT that was necessary for CDI; in here resided the IQ motif [3,6]. This placed renewed focus on CaM, previously thought to have been ruled out as a candidate, as the putative Ca²⁺ sensor. Subsequent studies confirmed that CaM supported CDI. Since IQ motifs can be found in proteins that bind CaM in a Ca²⁺-independent manner, the presence of an IQ motif in _1C led to the hypothesis that CaM interacted with Ca_V1.2 channels as a constitutive Ca²⁺ sensor [4]. This was subsequently confirmed by biochemical, imaging, and functional approaches that also showed that CaM interacts, both in a Ca²⁺-dependent and Ca²⁺-independent fashion, with multiple, additional sites in the _1C CT; these are more proximal than the IQ motif [7–12]. Two recent X-ray crystal structures have provided a glimpse of how Ca²⁺/CaM might bind to the IQ motif [13,14], but it is not clear that these models represent an accurate interpretation of how CaM interacts with the intact _1C subunit in the absence of a picture showing how CaM binds to these other sites.

Beyond defining roles for CaM and the IQ motif as the Ca²⁺-sensor, some details of the downstream inactivation machinery have emerged. Expression of mutant CaMs that cannot bind Ca²⁺ slows inactivation to a rate similar that measured when Ba²⁺ serves as the permeant cation [4,5]. This led to the hypothesis that Ca²⁺-free CaM (apoCaM) acts as a brake upon inactivation and that Ca²⁺ releases the brake to accelerate inactivation [9]. Functional assessment of a series of _1C mutants defective in binding CaM supported this hypothesis, since inactivation for these mutants was accelerated even in Ca²⁺-free conditions [11]. An EF hand motif in the _1C CT, proximal to the CaM binding pocket and the IQ motif, has been proposed to act as a signal transducer between the CaM-based Ca²⁺-sensing apparatus and the inactivation particle [11,15]. Several reports have suggested that the identity of this inactivation particle is the _1C cytoplasmic I–II linker [16,17]. In support of this idea, a complex of CaM and the _1C CT can bind the I–II linker [11]. The I–II linker is an attractive candidate for the inactivation particles since it is a major site for anchoring the calcium channel accessory β subunit [18], which has a strong influence on inactivation kinetics, but the specific details about its role remain undefined.

1.2. Ca²⁺/calmodulin-dependent regulation of Na⁺ channels
Recognition that voltage-gated Na⁺ channels contain an IQ motif within their CT, in a homologous position to the IQ motif in Ca²⁺ channels, prompted consideration that Na⁺ channels were also sensitive to Ca²⁺/CaM regulation [19]. Subsequent studies examining whether CaM regulates Na⁺ channels, however, have yielded conflicting results [20–23]. Reported effects upon the cardiac Na_v1.5 channel have been particularly discordant: individual studies found that Ca²⁺/CaM affects slow inactivation [20], stabilizes inactivation via interaction with the III–IV linker [24], hyperpolarizes the voltage dependence of activation [23], or has no effect [21]. This lack of a clear effect, in contrast to Ca²⁺/CaM-mediated CDI of Ca_V1.2 Ca²⁺ channels, may be reflected by the difference in the biochemistry of CaM interaction with Na⁺ channel CTs compared to CaM interaction with the _1C CT. In Na⁺ channels, the binding site for both apoCaM and Ca²⁺/CaM appears restricted to the region immediately surrounding the IQ motif and does not involve other sequences [24]. Moreover, CaM may not be the only sensor for Ca²⁺-regulation to Na⁺ channels. A putative EF hand motif in the Na_v1.5 CT has been proposed as a Ca²⁺ binding site and as a regulator of Ca²⁺-dependent effects [22,25]. This is controversial: the sequence for this Na_v1.5 EF hand departs from a canonical EF hand motif at a critical residue and a separate study failed to detect any Ca²⁺ binding [24].

1.3. Ca²⁺/calmodulin-dependent regulation of K⁺ channels
As with Ca²⁺ channels and Na⁺ channels, identification of putative IQ motifs in the CT of KCNQ1 K⁺ channels prompted a similar exploration whether these channels were sensitive to Ca²⁺/CaM regulation [26]. KCNQ1 is the pore-forming subunit of I_Ks, a major contributor to ventricular repolarization. That KCNQ1 is also the most commonly mutated locus in the arrhythmogenic Long QT Syndrome [27] generated additional interest in Ca²⁺/CaM regulation and its contribution to arrhythmias. Biochemical analysis showed that the mode of CaM interaction with KCNQ1 involves multiple regions over a relatively long sequence and does not appear restricted to either one of the two IQ motifs. Currents from mutant channels defective in Ca²⁺/CaM interaction or currents from wild-type channels recorded under Ca²⁺-free conditions showed prominent inactivation [28,29]. This suggests a model in which Ca²⁺/CaM relieves inherent channel inactivation and may explain earlier reports that Ca²⁺ increases the cardiac I_Ks current [30–32].

Not only does CaM affect channel gating, however, but functional and biochemical analysis of LQTS mutations in the KCNQ1 CT showed that disruption of CaM interaction with KCNQ1 interfered with subunit assembly and that the resultant channels generated very small currents. These results reflect that ion channel subunits associate early during channel biosynthesis [33,34], as has been previously shown for trafficking of neuronal SK K⁺ channels [35,36]. Thus, this influence upon KCNQ1 channel assembly emphasizes that CaM, in addition to providing Ca²⁺-regulation to mature channels at the cell surface, can also control various steps during ion channel biosynthesis, in addition to providing Ca²⁺-regulation to mature channels at the cell surface. Although not yet demonstrated in heart, regulation of Ca_V1.2 channel biosynthesis may also be an important role for CaM because of its constitutive interaction with _1C.

1.4. CaM regulation of ryanodine receptors
CaM also regulates the sarcoplasmic reticulum Ca²⁺ release channel, RyR2, the source of the Ca²⁺ that triggers contraction with each heart beat. How CaM binds to RyR2 and the consequent regulation of channel function is different from the manner described above for CaM interaction with and regulation of plasma membrane channels. In vitro experiments show that apoCaM and Ca²⁺/CaM have a single binding site on the large RyR2 cytoplasmic domain. This site does not resemble a consensus IQ motif [37]. CaM binding inhibits channel function, decreasing the P_o during single channel recordings by 60%. For the cardiac RyR2 channels, inhibition appears to be independent of Ca²⁺:CaM in the presence of submicromolar Ca²⁺ or mutant CaMs unable to bind Ca²⁺ also inhibit channel function. In contrast, the skeletal RyR1 channel is stimulated by apoCaM [38]. Thus it does not appear to afford Ca²⁺-sensitivity to mature RyR2 channels in the sarcoplasmic reticulum. Perhaps, the important role for CaM in RyR2 regulation is that it affords Ca²⁺-dependent control to aspects of channel biosynthesis, but this has not yet been explored.

1.5. Indirect regulation by CaM: activation of CaMKII
CaM also regulates ion channels through activation of Ca²⁺/CaM-sensitive enzymes, such as CaMKII. Since this kinase is sensitive to the frequency of Ca²⁺ transients, CaMKII is ideally suited to respond to changes in cardiac rhythm and therefore provides an additional mode of Ca²⁺-dependent regulation. CaMKII regulation of Ca_V1.2 channels is a major contributor to the positive force-frequency relationship of cardiac contraction or "staircase" effect [39], which describes the increased contraction strength obtained with faster heart rates and underlies improved cardiac performance seen during exercise [40]. The underlying mechanism is that increased frequencies of stimulation result in a CaMKII-dependent enhancement of the inward Ca²⁺ current [41–46]. Like CDI, this gating phenomenon requires Ca²⁺ influx (the enhancement is not seen when Ba²⁺ is used as charge carrier) and the phenomenon is therefore termed Ca²⁺-dependent facilitation (CDF).

This Ca²⁺-dependence resides in CaM [4] and two different CaMKII-mediated effects. First, the kinase's enzymatic activity is required; CaMKII inhibitors and non-hydrolyzable ATP analogs both eliminate CDF [47,48]. Several sites within the Ca_V1.2 _1C subunit [49–51] and one site in the C terminus of the accessory β2a subunit [52] have been proposed as the targets of CaMKII. Second, direct CaMKII interaction with Ca_V1.2 is necessary for CDF. CaMKII forms a complex with the Ca_V1.2 channel in heart and the kinase's activity is directly regulated by its interaction with the _1C CT. Disruption of the interaction between CaMKII and the _1C CT blocks CDF [49]. CaMKII has also been shown to interact with other intracellular domains of _1C and the CT of β2a [49,52], although the consequences of these interactions are not yet known. Nevertheless, the positioning of CaMKII near the major source of Ca²⁺ entry creates a tightly-looped, Ca²⁺-dependent feed-back mechanism whereby CaMKII acts as a local and dedicated integrator of Ca²⁺ signals to control myocyte excitability [49].

Specific structural features of CaMKII provide it with this ability to translate adjustments in the frequency of Ca²⁺ transients during changes in cardiac rhythm into activity-dependent alterations such as CDF. Activation of the kinase is initiated when Ca²⁺/CaM binds to an autoregulatory region (autoinhibitory peptide, AIP), which causes the removal of the pseudo-substrate domain from the catalytic site. At higher stimulation frequencies, autophosphorylation of a key threonine residue (Thr²⁸⁷ in the cardiac isoform) adjacent to the AIP makes subsequent kinase activity independent (autonomous) of Ca²⁺ and CaM [53] and increases the kinase's affinity for CaM by over 10,000-fold ("CaM trapping") [54]. These properties endow CaMKII with the ability to become persistently activated depending on the frequency of Ca²⁺ oscillations [55–58]. Autophosphorylation on Thr³⁰⁵ and Thr³⁰⁶ within the AIP prevents CaM binding and subsequent re-activation of the kinase [59].

The recent determination of the atomic structure of the CaMKII catalytic domain provides new insights into the mechanism of CaMKII activation and regulation by Ca²⁺/CaM [60]. The functional unit is a dimer of two catalytic domains in which the unliganded CaM-binding AIPs block access to the constitutively active catalytic sites (see Fig. 1). The key Thr²⁸⁷ residue sits at an elbow joining the AIP to the kinase domain. "Autophosphorylation" of the Thr is better appreciated as transphosphorylation of one subunit by the other in the dimeric unit when both are occupied and disinhibited simultaneously by Ca²⁺/CaM. In addition to trapping CaM on the AIP, autophosphorylation likely prevents the AIP from inhibiting the kinase and therefore leads to the persistent activation. Although this dimeric arrangement between two catalytic subunits and their two AIPs was unexpected given the models previously proposed for CaMKII assembly and activation, it is consistent with the extensive biochemical and functional data that have been previously obtained [61]. More importantly, it provides a basis for generating new models for how CaMKII may interact with targets, such as the _1C or β2a subunits of Ca_V1.2 channels.

View larger version (34K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Molecular mimicry model of CaMKII regulation of CaV1.2 and CDF. A. A CaMKII monomer with the critical Thr subject to autophosphorylation (Thr286 in the isoform) and the AIP indicated on left. The mimicry of the 1C CT (blue) for the AIP is shown on right. B. Sequence comparisons of 1C (amino acids 1644–1675), CaMKII (247–309), and β2a (485–502). The CaMKII interaction site on 1C is boxed. The autophosphorylation site on CaMKII (Thr287) and the CaMKII phosphorylation site on β2a (Thr498) are indicated. C. Arrangement of an activated CaMKII catalytic dimer in complex with the 1C CT and the β2a CT. The β2a CT (blue) replaces the AIP in one of the CaMKII catalytic domains (green). The interaction between β2a and the 1C I–II linker is also indicated. The 1C CT (red) replaces the AIP ion the other CaMKII catalytic domain (yellow). Figures A and B were created with DeepView/Swiss-PdbViewer v3.7 using coordinates in ID 2BDW in the Protein Data Bank.

 
Defining details for the interaction between CaMKII and _1C adds to our understanding of how CaMKII regulates Ca_V1.2 channels. The CaMKII interaction site on the _1C CT lies adjacent to the CaM-binding IQ motif; the reciprocal interaction site on CaMKII resides within the catalytic domain [49]. Although Ca²⁺/CaM and autophosphorylation of CaMKII is required for initiating the interaction with the _1C CT terminus and CaMKII, once bound to _1C, CaMKII remains tethered and no longer requires Ca²⁺/CaM to sustain the interaction. However, the activity of the tethered CaMKII retained its dependence upon Ca²⁺/CaM. After dephosphorylation, tethered CaMKII can be re-activated by Ca²⁺/CaM [49].

1.6. Molecular mimicry model for CaMKII interaction with ion channels
Herein is a model that builds upon a form of molecular mimicry to incorporate these observations. As shown in Fig. 1A, the _1C CT mimics the AIP, remaining stably associated with CaMKII and functioning as a pseudo-AIP. A novel aspect of this model is that the tethered CaMKII remains subject to Ca²⁺/CaM regulation through Ca²⁺ interaction with the CaM bound to the _1C IQ motif. In Fig. 1A, the actual AIP is depicted as displaced from the CaMKII catalytic domain, which is consistent with the finding that autophosphorylation of CaMKII is necessary for the initial interaction with the _1C CT [49]. An additional CaM molecule is modeled bound to the displaced AIP, since the CaMKII autophosphorylation required for its interaction with _1C would lead to CaM trapping.

A satisfying outcome of this model is that it provides a means to understand how CaMKII and CaM could both occupy adjacent "real estate" within the _1C CT, as suggested by the experiments showing that disruption of CaMKII interaction with _1C does not prevent CaM interaction [49]: considering the _1C CT domain as an AIP-like molecule, for which the interaction with both the CaMKII catalytic site and CaM in a defined region are well understood, offers a new framework to appreciate these interactions.

Molecular mimicry may also extend to the interaction between β2a and CaMKII (Fig 1B). Although the interaction site for β2a on CaMKII has not been identified and the reciprocal interaction site on β2a has not been mapped below a resolution of ~100 amino acids, a sequence in this region (which includes the CaMKII phosphorylation site at Thr⁴⁹⁸) also mimics the sequence around the CaMKII AIP [52]. The region of homology with CaMKII is shifted more N-terminal than the _1C-like region (Fig. 1B), and does not include the amino acids that contribute to CaM binding. Like CaMKII interaction with _1C, CaMKII autophosphorylation is also necessary for interaction with β2a. Thus, the AIP would likely be displaced when β2a is bound to CaMKII. Unlike _1C, however, the consequences on CaMKII activity for the interaction with β2a have not been determined, but likely differ from those due to interaction with _1C. The identification within the β2a C terminus of this interaction site and the discovery of a CaMKII phosphorylation site whose elimination prevents CDF is also noteworthy since it provides additional support for an emerging hypothesis that β subunit regulation of Ca²⁺ channel function requires contacts between the ₁ and β subunits exclusive of the well-characterized interaction between the ₁ subunit's AID (₁ interaction domain) and the β subunit's guanylate kinase (GK) domain [62,63].

Although speculative, this molecular mimicry model offers an attractive way to incorporate several disparate observations, such as explaining why CDF requires not only activation of CaMKII but also Ca²⁺/CaM interaction with the _1C IQ motif [4]. Also, it fits with the dimeric arrangement of CaMKII catalytic domains and the simultaneous interactions among CaMKII, _1C, and β2a, as follows (Fig. 1C): upon high frequency stimulation, one component of the CaMKII dimer associates with the _1C CT. As described above, CaMKII then remains associated with _1C and serves as a dedicated frequency detector. This CaMKII subunit is sensitive to the Ca²⁺/CaM regulation by the CaM bound to the _1C IQ motif. At elevated heart rates and the consequent increase in Ca²⁺ transients, transphosphorylation of the other CaMKII catalytic domain in the dimer would render it able to interact with the CT of β2a. Held in close proximity by its interaction with the _1C I–II intracellular loop [18], the β2a subunit would be well-poised for this interaction. The _1C and β2a subunits would then be targeted for phosphorylation by one of the two CaMKII subunits in this dimer or possibly by one of the other CaMKII subunits in a CaMKII dodecamer. Thus, this model explains the three apparently disparate requirements for CDF: Ca²⁺/CaM interaction with the IQ motif [4], interaction between CaMKII and the _1C CT [49], and the phosphorylation of β2a [52].

Parallels with the molecular mimicry model for CaMKII interaction with and regulation of Ca_V1.2 channels may be found in other cardiac ion channels. Cardiac Na⁺ channels (Na_v1.5) have also been shown to be regulated by CaMKII [21] and, like Ca_V1.2 channels, contain an IQ motif in their CT. Although never reported, CaMKII might also regulate I_Ks through interactions with KCNQ1 and its IQ motifs. The similarities in modes of Ca²⁺/CaM regulation of cardiac ion channels, as detailed above, suggest that aspects of CaMKII modulation may also be shared.

1.7. Other ion channels as potential targets of Ca²⁺-dependent regulation
Although this review highlights emerging concepts regarding Ca²⁺/CaM regulation of the Ca_V1.2 Ca²⁺ channel, KCNQ1 K⁺ channel, Na_v1.5 Na⁺ channel, and RyR2, the many other channels that contribute to the cardiac action potential or mediate other essential cellular processes may also be as yet unrecognized targets for Ca²⁺/CaM regulation. Several ion channels outside the cardiovascular system, including cyclic nucleotide-activated olfactory channels, EAG K⁺ channels, and NMDA receptors are modulated by CaMKII or directly by Ca²⁺/CaM [64–68]. It is therefore interesting to speculate that other cardiovascular channels, such as the HCN pacemaker channels (which are members of the cyclic nucleotide-activated channel family) or the HERG K⁺ channels (which are similar to EAG K⁺ channels) might be particularly promising candidates for future study.

	Acknowledgements

 
Supported by grants from the NIH and American Heart Association and the Irma T. Hirschl Monique Weill-Caulier Trust. G.S.P. is the Esther Aboodi Assistant Professor of Medicine.

	Notes

 
Time for primary review 31 days

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