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PERSPECTIVE

Ca²⁺ Regulation of Inositol 1,4,5-trisphosphate Receptors: Can Ca²⁺ Function without Calmodulin?

Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom

Received May 11, 2004; accepted May 13, 2004

	Abstract

Top Abstract Tethered CaM: Poised to... Ca2+ Regulation of Intracellular... References

 
All Ca²⁺ channels are regulated by Ca²⁺, a feature that allows them to respond to their own activity and to the activities of neighboring Ca²⁺ channels. Inhibition by Ca²⁺ protects cells from potentially hazardous increases in cytosolic [Ca²⁺], and stimulation can mediate facilitation and regenerative propagation of Ca²⁺ signals. Calmodulin is emerging as a key player in regulation of Ca²⁺ channels by Ca²⁺, but its role is more complex and more beautiful than might have been imagined.

View larger version (37K): [in this window] [in a new window]   Fig. 1. A–C, Ca2+ binding to CaM. A, structure of the C-terminal lobe of CaM with Ca2+ bound (PDB code 4CLN [PDB] ). B, Ca2+-binding loop of the third EF hand of CaM; the residue mutated to produce CaM with much reduced affinity for Ca2+ is shown in red. C, structures of apoCaM (blue; PDB code 1CFC [PDB] ) and Ca2+-CaM (red; PDB code 3CLN [PDB] ). D–F, regulation of Ca2+ channels by CaM. D, CaM tethered in the C-terminal tail of the L-type Ca2+ channels binds Ca2+ and thereby acquires the ability to interact with a second CaM-binding site through which CDI is initiated. E, for non–L-type Ca2+ channels the two lobes of Ca2+ are positioned to respond to different Ca2+ signals, the C-lobe preferentially detects Ca2+ (red) passing through the channel, whereas the N-lobe responds to global Ca2+ signals (blue). F, in RyR1, the tethered C-lobe of CaM moves toward the N-terminal of a CaM-binding region when it binds Ca2+ (pink), whereas the N-lobe interacts with a site on a neighboring subunit. The C-lobe provides the essential Ca2+ sensor and its movement leads to channel inhibition, possibly by causing rearrangement of the interactions between the subunits. The Cys residues that also mediate cross-linking of subunits are also shown.

The N- and C-terminal lobes of CaM are similar but not identical. In the absence of Ca²⁺, the C-terminal sites are more open than those in the N-lobe, they have 10-fold greater affinity for Ca²⁺, and Mg²⁺ dissociates more rapidly from them. The latter is important because at resting cytosolic [Ca²⁺], most of the Ca²⁺-binding sites of CaM are probably occupied by Mg²⁺, which must dissociate before Ca²⁺ can bind. The C-lobe is therefore best equipped to respond rapidly to increases in cytosolic [Ca²⁺]. Ca²⁺ binding causes twisting of the helices within the EF hand (they become almost perpendicular to each other) and, because helices from each EF hand move in concert, binding of Ca²⁺ to one EF hand promotes Ca²⁺ binding to its partner. There are also interactions between lobes and a further increase in Ca²⁺ affinity when the target protein binds; Ca²⁺ binding is thus positively cooperative (Ikura, 1996) and the affinity of CaM for Ca²⁺ is tuned by its association with target proteins (Jurado et al., 1999). These Ca²⁺-evoked conformational changes (Fig. 1C) cause CaM to expose a concave hydrophobic surface (Vetter and Leclerc, 2003) to which target proteins can bind via positively charged amphiphilic -helices (Rhoads and Friedberg, 1997).

Not all interactions with CaM require Ca²⁺ (Jurado et al., 1999). CaM is permanently associated with some proteins, some reversibly associate only with apoCaM, and others bind CaM whether or not it has Ca²⁺ bound. Accumulating evidence suggests that Ca²⁺-independent anchoring of CaM to Ca²⁺-regulated channels may be an important means of ensuring that the Ca²⁺ sensor is placed to allow rapid responses to changes in [Ca²⁺] (Xia et al., 1998; Liang et al., 2003; Zamponi, 2003). IQ motifs (IQxxxRGxxxR) commonly mediate Ca²⁺-independent binding to CaM (Rhoads and Friedberg, 1997), but they are not the only sequences to mediate such interactions, nor is binding of CaM to all IQ motifs Ca²⁺-independent (Jurado et al., 1999). An important point is exemplified by glycogen phosphorylase b kinase with which CaM is permanently associated: the interaction is mediated by two distinct sites in the subunit, neither of which binds CaM in the absence of Ca²⁺, yet together they are sufficient to mediate a stable interaction even in the absence of Ca²⁺ (Dasgupta et al., 1989). Such synergistic binding highlights the difficulty of trying to identify physiologically important CaM-binding sites using peptide fragments of target proteins. Intimate associations between CaM and its targets tend also to be resistant to disruption by conventional or peptide antagonists (Xia et al., 1998; Krupp et al., 1999; Peterson et al., 1999). Furthermore, peptides derived from sites known to bind apoCaM in the native protein often bind preferentially to Ca²⁺-CaM in isolation (Jurado et al., 1999). Each of these features contributes to the considerable difficulties associated with defining the roles of CaM in mediating Ca²⁺ regulation of channels.

	Tethered CaM: Poised to Regulate Voltage-Gated Ca2+ Channels

Top Abstract Tethered CaM: Poised to... Ca2+ Regulation of Intracellular... References

 
CaM tethered to L-type Ca²⁺ channels mediates Ca²⁺-dependent inactivation (CDI) (Peterson et al., 1999; Erickson et al., 2001). CDI is abolished in cells expressing CaM₁₂₃₄, indicating that Ca²⁺-insensitive CaM effectively competes with native CaM for the tethering site but fails to mediate the response to Ca²⁺. Selective disruption of Ca²⁺ binding to either the N-lobe (CaM₁₂) or C-lobe (CaM₃₄) shows that Ca²⁺ binding to the C-lobe of CaM is required for CaM CDI. Within the C-terminal tail of the principal (_1C) subunit of the L-type Ca²⁺ channel, three sequences, including an IQ motif, are capable of binding CaM (Tang et al., 2003). Exactly which of these sites contribute to CaM tethering and CDI remains controversial (Erickson et al., 2001; Pitt et al., 2001; Tang et al., 2003). Together, they mediate binding of a single CaM molecule, probably tethered by its N-lobe. Although Ca²⁺-insensitive CaM₁₂₃₄ binds to this region, it requires basal levels of Ca²⁺, suggesting that Ca²⁺ binding to the channel modulates its ability to tether CaM (Pitt et al., 2001). The C-lobe of CaM, when it binds Ca²⁺, then interacts with different residues to initiate CDI. Figure 1D summarizes these interactions showing that tethered CaM migrates within the CaM-binding region when its C-lobe binds Ca²⁺ and thereby initiates CDI.

A similar mechanism underlies CDI of other voltage-gated Ca²⁺ channels but with an intriguing difference: whereas Ca²⁺ must bind to the C-lobe of CaM for inactivation of L-type channels, it binds to the N-lobe to inactivate P/Q, R, and N-type channels (Liang et al., 2003). The difference allows CDI of L-type channels to be driven by local Ca²⁺ signals (detected by the C-lobe with its ability to bind Ca²⁺ quickly; see above), whereas slower binding to the low-affinity N-lobe tailors CDI of the other Ca²⁺ channels to global Ca²⁺ signals (Fig. 1E).

For P/Q-type channels, there is an additional wrinkle. Global Ca²⁺ signals detected by the N-lobe of tethered CaM mediate CDI, whereas local Ca²⁺ signals detected by the C-lobe cause rapid Ca²⁺-dependent facilitation (DeMaria et al., 2001). Such versatility is possible only because the two lobes of CaM respond differently to rapid increases in [Ca²⁺] and because CaM can be tethered near the mouth of the channel, where it is optimally poised both to detect and regulate channel activity. Voltage-gated Ca²⁺ channels thus provide exquisite examples of how spatial organization and the kinetics of Ca²⁺ sensors can be tailored to allow selective decoding of Ca²⁺ signals.

Tethered CaM also mediates Ca²⁺ regulation of K⁺ channels (Xia et al., 1998). For other channels too, including TRP proteins, cyclic nucleotide-gated channels, and N-methyl-D-aspartate receptors, CaM is involved in Ca²⁺ regulation, and although the mechanisms may differ, a common theme is disruption of protein-protein interactions by Ca²⁺-CaM.

	Ca2+ Regulation of Intracellular Ca2+ Channels

Top Abstract Tethered CaM: Poised to... Ca2+ Regulation of Intracellular... References

 
Both major families of intracellular Ca²⁺ channels [i.e., inositol 1,4,5-trisphosphate receptors (IP₃R) and ryanodine receptors (RyR)] are biphasically regulated by cytosolic Ca²⁺. Such regulation is profoundly important in that Ca²⁺ binding ultimately determines whether the channels will open: other signals exert their effects solely by modulating the effects of Ca²⁺ (Adkins and Taylor, 1999). But for neither channel is the role of CaM clearly resolved (discussed in Nadif Kasri et al., 2002; Taylor and Laude, 2002). Both channels bind apoCaM and Ca²⁺-CaM, and CaM undoubtedly modulates their sensitivity to Ca²⁺, but both channels also bind Ca²⁺ directly. For simplicity, we consider only Ca²⁺ inhibition.

After years during which many different CaM-binding sites were proposed to exist on RyR1, the consensus now is that each subunit binds both apoCaM and Ca²⁺-CaM, but the sites overlap such that apoCaM is tethered by its C-lobe and then shifts within the overlapping sites when it binds Ca²⁺ (Rodney et al., 2001b; Zhang et al., 2003). The shift allows it to inhibit the channel, and CaM₁₂ is as effective as wild-type CaM in mediating the inhibition (Rodney et al., 2001a). The N-lobe of CaM, which is required for inhibition even though it need not bind Ca²⁺, seems to interact with a different site on a neighboring subunit: CaM may thereby tie one RyR1 subunit to another (Zhang et al., 2003). This is interesting because Cys residues near these CaM-binding sites also cross-link RyR1 subunits and mediate effects of oxidation on channel opening. One appealing suggestion (Xiong et al., 2002) is that CaM is tethered by both lobes and edges along its binding site when its C-lobe binds Ca²⁺, the movement then causing rearrangement of the interaction between subunits, leading ultimately to channel inhibition (Fig. 1F).

For IP₃R, the situation is more confusing. Ca²⁺ inhibits all IP₃Rs. There is evidence that such inhibition may result from Ca²⁺ binding directly to the receptor, but competing evidence (reviewed in Taylor and Laude, 2002) implicates additional Ca²⁺-binding proteins, and CaM is the most likely candidate (Adkins et al., 2000), not least because it has been reported to restore Ca²⁺-inhibition to purified IP₃R (Michikawa et al., 1999). Because IP₃R1 has received most attention, we consider only this subtype. A split site near the N terminus binds both apoCaM and Ca²⁺-CaM and seems to mediate Ca²⁺-independent inhibition of IP₃ binding (Patel et al., 1997). It is curious, however, that CaM has never been shown to inhibit IP₃R function in the absence of Ca²⁺. A more central site forms a typical Ca²⁺-CaM binding site and mutation of its central Trp residue reduces its ability to bind CaM (Yamada et al., 1995). In functional assays, this mutation has consistently failed to affect inhibition of IP₃R by Ca²⁺ or CaM (Zhang and Joseph, 2001; Nosyreva et al., 2002). We have suggested that this region also binds apoCaM and that the point mutation fails to completely abolish CaM binding (Adkins et al., 2000). An article in this issue of Molecular Pharmacology (Nadif Kasri et al., 2004) explores this further and shows (rather like results from RyR1) that overlapping sites within this area bind both apoCaM and Ca²⁺-CaM, such that Ca²⁺ binding might cause CaM to move toward the C-terminal of the site. The newly revealed complexity of this site re-ignites the possibility that it may contribute to CaM-regulation of IP₃R, although its absence from IP₃R3, which is also inhibited by CaM, would then be difficult to explain. A third site, which also binds only Ca²⁺-CaM, is created only after removal of the S2 splice site of IP₃R1 (Lin et al., 2000); its role is unknown. Clearly, Ca²⁺-CaM inhibits IP₃Rs, but the sites through which it exerts that inhibition are unresolved, and is it unclear whether CaM is exclusively responsible for Ca²⁺ inhibition. We have suggested (Taylor and Laude, 2002; Taylor et al., 2004), in analogy with L-type Ca²⁺ channels and RyRs, that CaM may be constitutively tethered by one lobe to IP₃R1 (possibly via the N-terminal Ca²⁺-independent CaM-binding site); then, when the second lobe binds Ca²⁺, it binds to another site on a different subunit to inhibit channel opening. However, we need better tools to test such speculations.

At first sight, suramin, which displaces both Ca²⁺-CaM and apoCaM from RyR1 (Papineni et al., 2002) looks like a promising means of disentangling the complex effects of CaM on IP₃R. In this issue of Molecular Pharmacology, Nadif Kasri et al. (2004) show that suramin does indeed block all CaM binding to IP₃R irrespective of the free [Ca²⁺]. However, suramin is rather like heparin in that it behaves as a competitive antagonist of IP₃; it reduces the sensitivity of Ca²⁺ release to IP₃ and it displaces IP₃ from its binding site. The authors considered this possibility, of course, and claimed to eliminate it by demonstrating that suramin effectively reduces [³H]IP₃ binding to the N-terminal fragment (residues 1–581) that includes a CaM-binding site, but not to a shorter fragment (226–581). The observation is correct, but the conclusion is not. Because the shorter fragment binds IP₃ with much greater affinity (Uchiyama et al., 2002), higher concentrations of antagonist are required to displace [³H]IP₃ from it. In our hands, similar fragments of IP₃R1 (1–604 and 224–604) differ by about 40-fold in their affinities for IP₃ (K_D = 5.98 ± 1.13 and 0.14 ± 0.08 nM, respectively). Suramin displaces [³H]IP₃ from both, although higher concentrations are required to displace it from the smaller fragment (IC₅₀ = 10.3 ± 0.6 and 129 ± 12 µM, for the long and short fragments, respectively; Fig. 2). After correcting for the different affinities for IP₃, it is clear that both fragments— one with and one without the CaM-binding site— bind suramin with similar affinity (K_D = 9.24 ± 0.6 and 20.7 ± 2.0 µM, for the long and short fragments, respectively). Plainly suramin is yet another of the low-affinity, polysulfated competitive antagonists of the IP₃R.

View larger version (17K): [in this window] [in a new window]   Fig. 2. Binding of suramin to N-terminal fragments of IP3R1. Displacement of [3H]IP3 (0.7 nM) from N-terminal fragments (, residues 224–604; , 1–604) of IP3R1 by suramin (means ± S.E.M, n = 3).

Despite its limitations, what can suramin tell us about the effects of CaM on IP₃R? At concentrations that prevent IP₃Rs from binding to CaM-Sepharose, suramin does not affect biphasic regulation of IP₃R by cytosolic Ca²⁺, although the extent of the inhibition was surprisingly small. This might suggest that CaM cannot provide the Ca²⁺ sensor that mediates Ca²⁺ inhibition, but it is notoriously difficult (see above) to pharmacologically disrupt the association of endogenous CaM with its targets. In none of these experiments was suramin shown to dissociate endogenous CaM from full-length IP₃Rs. More interesting is the observation that CaM₁₂₃₄ effectively mimics the effects of CaM: both potentiate Ca²⁺ inhibition (Nadif Kasri et al., 2004). This surprising result is very different from the effect of CaM₁₂₃₄ on other Ca²⁺-regulated channels, where it behaves as an antagonist by displacing endogenous Ca²⁺-responsive CaM. For IP₃R1, then, the effects of CaM are wholly independent of its ability to bind Ca²⁺, but the CaM can inhibit only when the IP₃R has bound Ca²⁺. Many sites to which Ca²⁺ binds on IP₃R1 (Sienaert et al., 1997) could mediate the effect of Ca²⁺, but where does the CaM bind? The N-terminal CaM-binding site deserves consideration, but in the intact IP₃R, both CaM binding to it (unlike the "apoCaM"-binding site of L-type channels) and the effect of CaM on IP₃ binding are entirely unaffected by Ca²⁺ (Patel et al., 1997). This site might therefore be responsible for CaM tethering, but it seems unlikely to mediate a response to Ca²⁺. Perhaps, in analogy with the behavior of CaM at other Ca²⁺-regulated channels, the work from Nadif Kasri et al. should prompt us into looking for another apoCaM-binding site, access to which is regulated by Ca²⁺ binding to the IP₃R.

	Footnotes

 
This work was supported by the Wellcome Trust.

Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

DOI: 10.1124/mol.104.002592.

ABBREVIATIONS: CaM, calmodulin; CDF, Ca²⁺-dependent facilitation; CDI, Ca²⁺-dependent inactivation; IP₃R, inositol 1,4,5-trisphosphate receptor; RyR, ryanodine receptor.

Address correspondence to: Colin W. Taylor, Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK. E-mail: cwt1000{at}cam.ac.uk

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This Article Abstract Full Text (PDF) Correction An erratum has been published Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rossi, A. M. Articles by Taylor, C. W. Search for Related Content PubMed PubMed Citation Articles by Rossi, A. M. Articles by Taylor, C. W.