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Biological Research

versión impresa ISSN 0716-9760

Biol. Res. v.37 n.4 Santiago  2004 


Biol Res 37: 577-582, 2004


Calmodulin and Calcium-release Channels


Laboratorium voor Fysiologie, K.U.Leuven Campus Gasthuisberg O/N, Herestraat 49, B-3000 Leuven, Belgium

Dirección para Correspondencia


Calmodulin (CaM) is a ubiquitous cytosolic protein that plays a critical role in regulating cellular functions by altering the activity of a large number of ion channels. There are many examples for CaM directly mediating the feedback effects of Ca2+ on Ca2+ channels. Recently the molecular mechanisms by which CaM interacts with voltage-gated Ca2+ channels, Ca2+-activated K+ channels and ryanodine receptors have been clarified. CaM plays an important role in regulating these ion channels through lobe-specific Ca2+ detection. CaM seems to behave as a channel subunit. It binds at low [Ca2+] and undergoes conformational changes upon binding of Ca2+, leading to an interaction with another part of the channel to regulate its gating. Here we focus on the mechanism by which CaM regulates the inositol 1,4,5-trisphosphate receptor (IP3R). Although the IP3R is inhibited by CaM and by other CaM-like proteins in the presence of Ca2+, we conclude that CaM does not act as the Ca2+ sensor for IP3R function. Furthermore we discuss a novel Ca2+-induced Ca2+-release mechanism found in A7r5 (embryonic rat aorta) and 16HBE14o- (human bronchial mucosa) cells for which CaM acts as a Ca2+ sensor.

Key words: calmodulin, calcium channels, inositol 1,4,5-trisphosphate receptor.



Highly regulated changes in the free concentration of cytosolic Ca2+ control biological processes as diverse as muscle contraction, fertilization, cell proliferation and apoptosis. Many of these cellular effects are modulated by calmodulin (CaM), a prototypical Ca2+-sensor protein (Saimi and Kung, 2002) (See also E. Carafoli, "Calcium signalling: an historical account," in this issue).

Among the numerous target proteins of CaM are different types of important proteins of the Ca2+-signalling pathways and in particular Ca2+-permeable ion channels. At the plasma membrane voltage-gated Ca2+ channels (VGCCs), cyclic nucleotide-gated channels, N-methyl-D-aspartate receptors, and the transient receptor potential channel family (TRP) were shown to be tightly regulated by CaM (reviewed in Saimi and Kung, 2002). At the level of the endoplasmic reticulum, Ca2+ release through both the ryanodine receptor (RyR) and the inositol 1,4,5-trisphosphate receptor (IP3R) is also controlled by direct binding of CaM to these channels. For some of these Ca2+ channels the molecular mechanism by which CaM acts has been extensively studied and will be discussed in more detail in this review.

The VGCCs are multimeric Ca2+ channels that are activated upon membrane depolarisation. Ca2+ entry via VGCCs can be regulated by Ca2+- and voltage-dependent inactivation mechanisms (Hofmann et al., 1999). Recently it became clear that CaM is a major player in these feedback mechanisms (Liang et al., 2003; Zamponi, 2003). A bi-dentate anchoring of CaM to several types of VGCCs mediates their Ca2+-dependent inactivation. For L- type Ca2+ channels, apocalmodulin (apoCaM) is tethered via its N-terminal domain to the channel. Upon binding of Ca2+ to the C-lobe of CaM this C-lobe will bind to a different site on the channel and cause inactivation. Interestingly, the non-L-type Ca2+ channels (P/Q-, R-and N-type channels) were shown to have a similar feedback regulation by CaM but here the C-lobe is tethered to the channel proteins while the N-lobe is transmitting the Ca2+ signal.

Small-conductance Ca2+-activated K+ channels are homotetrameric proteins that use CaM as their Ca2+-sensing subunit in a similar way as the non-L-type Ca2+ channels (Schumacher et al., 2001; Xia et al., 1998).

RyRs are homotetrameric intracellular Ca2+-release channels encoded by three different genes (Furuichi et al., 1994). All three isoforms are inhibited by CaM and apoCaM is a partial agonist of RyR1 and RyR3 (Yamaguchi et al., 2001). Different CaM-binding sites were found on the RyRs, binding apoCaM or Ca2+CaM. Two sites were recently found to play a major role in the regulation of the RyR1 by CaM. One high-affinity site (AA. 3614-3643) was found to be an overlapping binding domain for both Ca2+CaM and apoCaM, which only binds the C-lobe of CaM. Upon binding of Ca2+ the C-lobe is shifted towards the N-terminal part of this domain (Rodney et al., 2001). A second site only binds the N-lobe of CaM, independently of the [Ca2+] but dependently on the position of the C-lobe (Xiong et al., 2002). This molecular binding mechanism explains the dual regulation of the RyR1 by CaM in the presence or absence of Ca2+ (Xiong et al., 2002). For the RyR2 a CaM-binding site (AA. 3583-3603) was found that was similar to the overlapping apoCaM- and Ca2+CaM-binding site of RyR1, and which was responsible for the inhibitory effects of Ca2+CaM (Yamaguchi et al., 2003).

The general picture that emerges is that CaM is involved in the direct feedback of Ca2+ on ion channels and particularly Ca2+ channels. In many cases CaM behaves as a channel subunit, interacting with the channel at low [Ca2+]. Upon binding of Ca2+, CaM undergoes conformational changes to interact with a different part of the channel thereby regulating its gating. This mechanism by which CaM acts as a Ca2+ sensor for different types of ion channels seems to be widespread. CaM interacts in a bipartite manner with ion channels: one CaM lobe mediating constitutive binding and the other transmitting the Ca2+-dependence. Such lobe-specific detection provides a compact means to decode local Ca2+ signals. The situation may, however, be different for the second family of intracellular Ca2+-release channels, the IP3Rs. This will be discussed in detail below.


IP3Rs are ubiquitous intracellular Ca2+-release channels that are activated upon binding of IP3 and regulated in a complex way by Ca2+. Low cytosolic [Ca2+] stimulates IP3R activity while higher cytosolic [Ca2+] is inhibitory. The positive regulation of the IP3R by Ca2+ may be largely due to a direct binding of Ca2+ to the receptor (Miyakawa et al., 2001). However the mechanism by which Ca2+ inactivates IP3Rs is less clear.

CaM is the only protein to have emerged so far as a potential inhibitory Ca2+ sensor, but the exact nature of its involvement remains unclear. CaM has been shown to inhibit the activity of the three IP3R isoforms (IP3R1-3) in a Ca2+-dependent manner (reviewed in Nadif Kasri et al., 2002; Taylor and Laude, 2002).

Three CaM-binding sites have been described for the IP3R1: a low-affinity complex site near the N-terminus of the IP3R1 (AA. 49-81 and AA. 106-128) that essentially binds CaM in a Ca2+-independent way; a high-affinity site in the regulatory domain (AA. 1564-1585) that mainly binds Ca2+CaM; and a third site that only appears after splicing out of the S2 splice domain (i.e. in peripheral tissues) (Nadif Kasri et al., 2002; Taylor and Laude, 2002).

It was originally thought that CaM mediates the Ca2+-dependent inactivation of IP3Rs due to its interaction with the Ca2+-dependent CaM-binding site in the regulatory domain (Yamada et al., 1995). However, a major role for this site would be difficult to reconcile with two studies in which mutation of a critical tryptophan residue largely eliminated Ca2+-dependent CaM binding but did not prevent inactivation of IP3Rs by Ca2+ (Nosyreva et al., 2002; Zhang and Joseph, 2001). Other evidence against this hypothesis is the observation that IP3-induced Ca2+ release (IICR) is equally inhibited by CaM for IP3R3, which clearly lacks the high-affinity site in the regulatory domain (Adkins et al., 2000; Missiaen et al., 2000).

It was then suggested that the N-terminal Ca2+-independent CaM-binding site could be involved in inhibiting IICR by an allosteric inhibition of IP3 binding (Adkins et al., 2000). Inhibition of IP3 binding by CaM was reported for all three IP3R isoforms (Vanlingen et al., 2000). Unlike the effects of CaM on IICR however, the effects on IP3 binding were found to be Ca2+ independent. This discrepancy can be explained by the large conformational change of the IP3R in the presence of Ca2+. Electron microscopy of the IP3R demonstrated that the conformation of the IP3R dramatically changes in the presence of Ca2+ from a closed "square-like" to an open "windmill" structure (Hamada et al., 2003). It is conceivable that CaM only inhibits IICR when the IP3R is in the "windmill" configuration. This mechanism could provide a tonic regulation of IP3R activity, and would also explain the low IP3 sensitivity of IICR in neuronal tissues where CaM is highly expressed.

Strong support for the latter hypothesis came from our recent data that CaM1234, a mutant CaM that does not bind Ca2+, has the same effects on IICR than CaM (Nadif Kasri et al., 2004a). These data would imply that CaM did not act as a Ca2+ sensor for the IP3R and that the Ca2+ dependence is due to a direct effect, independent of CaM.

Suramin, a polysulphonated naphtylurea, that has been shown to interact with the CaM-binding sites of the RyR and thereby to counteract the effects of CaM (Papineni et al., 2002), also interacted with the Ca2+-dependent and Ca2+-independent CaM-binding sites on the IP3R. Suramin mimicked the inhibitory effect of CaM by lowering the apparent affinity for IP3 (Nadif Kasri et al., 2004b). These data suggest that suramin as well as CaM interrupted an intramolecular interaction between the N-terminal 1-225 AA. of IP3R1 and another domain of the IP3R1, which is not yet identified.


A family of neuronal Ca2+-binding proteins (CaBPs) sharing significant homology in sequence and structure with CaM has recently been described in retina and brain (Haeseleer et al., 2002). These proteins belong to the super-family of neuronal Ca2+-sensor proteins, which have been shown to be involved in neuronal signalling (Burgoyne and Weiss, 2001). Unlike CaM, one or two of the EF-hand Ca2+-binding domains in CaBPs are non-functional. CaBP1 has been shown to bind to the N-terminus of the IP3R in a Ca2+-dependent manner. Furthermore it was reported that CaBP1 activated Ca2+ release through IP3Rs, independently of IP3 (Yang et al., 2002).

We investigated the interaction of CaBP1 with IP3Rs, and their functional effects on IICR. In contrast to the previous study (Yang et al., 2002) we found a Ca2+-independent interaction between CaBP1 and the most N-terminal CaM-binding domain (AA. 49-81) of IP3R1. Using several experimental paradigms we demonstrated a decrease in the sensitivity of IICR. Our results suggest that CaBP1 can behave as an endogenous regulator of the IP3R and may serve to tune the sensitivity of the IP3R for IP3 (Nadif Kasri et al., 2004). It is however excluded that CaBP1 could serve as a Ca2+ sensor for the IP3R, as we found that a Ca2+-independent mutant had similar effects on IP3R function.

Although similar to CaM, CaBP1 possesses unique properties, which may provide another level of IP3R regulation. As CaBPs bind to the N-terminal CaM-binding site, it is possible that the N-terminal CaM-binding site of IP3R would preferentially bind CaBP in vivo instead of CaM.

Interestingly, CaBP1 showed specificity for IICR since CaBP1 had no effect on RyR activity (S. Hamilton, personal communication). The latter finding is not surprising since the affinity of the interaction between CaBP1 and RyR1, unlike that between CaM and RyRs, is very low. Thus, in neurons that express both IP3Rs and RyRs, CaBP1 may serve to specifically inhibit IICR whereas CaM may target RyRs.

A similar Ca2+-independent modulation by CaBP1 was also observed for the P/Q-type VGCC (Lee et al., 2002). CaBP1, in addition to CaM, may therefore have an important role in the direct modulation of different Ca2+ channels in neurons.


Neither CaM nor CaBP1 act as Ca2+ sensors for the inhibition of IICR, since the Ca2+-independent mutants of these proteins also inhibit the IP3R. We have however found in A7r5 (embryonic rat aorta) and 16HBE14o- (human bronchial mucosa) cells a novel Ca2+-release mechanism that was not blocked by inhibitors of IP3Rs nor of RyRs, and that was functioning as a Ca2+-induced Ca2+-release pathway (CICR) with CaM as the Ca2+ sensor (Nadif Kasri et al., 2003). We concluded that A7r5 and 16HBE14o- cells express a novel type of CICR mechanism that is silent in normal resting condition due to inhibition by CaM but becomes activated by a Ca2+-dependent dissociation of CaM (Fig. 1). This CICR mechanism, which may also be regulated by members of the neuronal Ca2+-sensor proteins family, may provide an additional route for Ca2+ release that could allow for amplification of small Ca2+ signals. We could not yet identify the protein responsible for this CICR mechanism but it could represent a TRP-like Ca2+ channel such as polycystin-2 or vanilloid receptor-1. These two members of the TRP family were recently found to act as intracellular Ca2+-release channels (Liu et al., 2002; Somlo and Ehrlich, 2001).


The general picture that emerges is that CaM plays an important role in regulating a diversity of ion channels including various types of Ca2+ channels through lobe-specific Ca2+ detection. Although the general regulatory mechanism of CaM seems to be widespread, many variations with respect to the molecular mechanisms have been found.

Whereas for many types of Ca2+ channels including the RyR, CaM effectively operates as the Ca2+ sensor, this seems not to be the case for the IP3R. The molecular mechanism by which CaM interacts with the IP3R is still unknown. Our recent observations concerning CaM1234 have however provided new insights. Since CaM1234 was equally efficient as CaM for the inhibition of IICR, we concluded that CaM cannot be the Ca2+-sensor protein. An interesting observation concerned the role of CaBPs in regulating the IP3R. From two reports (Haynes et al., 2004; Nadif Kasri et al., 2004) it was concluded that CaBP1 interacted with the N-terminal CaM-binding site on the IP3R. Apparently the N-terminal CaM-binding site on the IP3R may have a higher affinity for other members of the neuronal Ca2+-binding protein family than for CaM. Therefore it will be interesting, in the future, to find the physiological relevant binding protein and binding characteristics for this site.

While CaM did not act as a Ca2+ sensor, it could possibly play a more important role in the intramolecular interaction of the IP3R between the N- and C-terminal domains. Moreover, CaM could act in a more indirect way on IP3R function through possible effects on the phosphorylation status of the IP3R (Vermassen et al., 2004).


Figure 1. CICR mechanism in A7r5 and 16HBE14o- cells. A novel type of CICR mechanism in A7r5 and 16HBE14o- cells was not blocked by inhibitors of IP3Rs or RyRs. ATP dose-dependently stimulated the CICR mechanism, whereas 10 mM MgCl2 abolished it. CICR was not affected by exogenously added CaM but strongly inhibited by CaM1234. Other proteins of the family of the neuronal Ca2+-binding proteins such as Ca2+-binding protein-1 (CaBP1) and neuronal Ca2+-sensor-1 (NCS1) were equally potent for inhibiting the CICR. Removal of the endogenous CaM using a CaM-binding peptide prevented subsequent activation of the CICR mechanism.


In A7r5 and 16HBE14o- cells we found a novel type of CICR mechanism in which CaM plays an important role as an endogenous Ca2+-sensor protein. CaM is an essential component for activating this mechanism. Displacement of the endogenous CaM by the Ca2+-insensitive CaM1234 or by a high-affinity CaM-binding peptide completely abolished the activation of this CICR mechanism. Although the identity of this novel CICR mechanism is unknown, its properties are in very good agreement with the general role of CaM as a feedback regulator of most cellular Ca2+ channels.


Work performed by the authors was supported by grant G.0210.03 (to H.D.S. and J.B.P.) of the Fund for Scientific Research Flanders (Belgium), and by Grant GOA/2004/07 from the Concerted Actions of the K.U. Leuven (to L.M., H.D.S., G.C. and J.B.P.). We are also grateful for the support by the Interuniversity Poles of Attraction Programme-Belgian State, Prime Minister's Office, Federal Office for Scientific, Technical, and Cultural Affairs, IUAP P5/05.


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Corresponding author: Humbert De Smedt, Laboratorium voor Fysiologie, K.U.Leuven Campus Gasthuisberg, Herestraat 49, B-3000 LEUVEN, Belgium. Tel: 0032 16 34 57 25, Fax: 0032 16 34 59 91, E-mail:

Received: January 15, 2004. Accepted: March 22, 2004.


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