Review articleCalmodulin binding proteins provide domains of local Ca2+ signaling in cardiac myocytes
Research highlights
► Calmodulin (CaM) acts as a local Ca2+ sensor with a limited range of action. ► Ca2+-sensitive ion channels are regulated by dedicated and promiscuous CaMs. ► CaM modulates the sensitivity of CaMKII and calcineurin to local Ca2+ signals.
Introduction
Calmodulin (CaM) is a central mediator of Ca2+-dependent signaling. CaM acts as the Ca2+ sensor for many ion channels and signaling pathways. Here, we will review aspects of CaM's biochemistry and targeting that enable it to transduce local Ca2+ signals into specific cellular outputs in cardiac myocytes.
Section snippets
CaM biochemistry
The biochemistry of CaM has important implications for how it regulates diverse local Ca2+ signaling pathways. CaM binds Ca2+ with an average apparent Kd ~ 5 μM, significantly higher than the range of 0.1–1 μM [Ca2+] generally seen in bulk cytosol of cardiac myocytes. Thus it is initially surprising that CaM is regulated by physiologic [Ca2+], but as we will see, local [Ca2+] near channels that pass Ca2+ can be much higher. CaM has a dumbbell-like structure, with 2 EF-hand Ca2+ binding sites at
CaM availability and signals in cardiac myocytes
Total CaM concentration is ~ 6 μM in isolated cardiac myocytes [13], [14]. While this may appear to be plenty to activate its targets, more than 90% of CaM in the cell is prebound, even at resting [Ca]i. Indeed, studies in other cell types have indicated that free CaM is only ~ 50 nM, making CaM a limiting factor in Ca2+ signaling [7]. Wu and Bers used null-point titration approaches with fluorescently labeled CaM to assess free CaM levels in myocytes [15]. Consistent with studies in other cell
Local CaM regulation of ion channels
Calmodulin has been shown to regulate a variety of ion channels in cardiac myocytes. Here, we will focus on CaM's regulation of L-type Ca2+ channel, ryanodine receptor and IP3 receptor as these have been well studied and exhibit multiple modes of CaM regulation. A key emerging theme for these channels is regulation by both “dedicated” and “promiscuous” CaM (Fig. 1). “Dedicated” CaM binds stoichiometrically to the channel (even at resting [Ca]i) and participates in direct channel regulation. On
Local CaM signals modulate kinase and phosphatase activities
While dedicated CaM at ion channels is typically regulated by a local Ca2+ signal, it appears that the promiscuous CaM coupled to Ca2+ signaling pathways may transduce a wider array of Ca2+ signals. CaM binding proteins exhibit a wide range of affinities for CaM, with dissociation constants ranging from 2 pM to 100 nM [11]. As discussed above, the affinity of the target protein for Ca-CaM will tune its Ca2+-dependence, with greater Ca2+ sensitivity for proteins that bind Ca-CaM tightly. Song et
Conclusions
Despite being the Ca2+ sensor for many different pathways, CaM is able to transduce variations in the location and magnitude of Ca2+ signals into specific cellular outputs. At the biochemical level, the different Ca2+ sensitivities and kinetics of CaM's C- and N-lobes, together with the affinity of the target protein for Ca-CaM are key determinants of how this signal will be processed. In most cases, CaM acts either as a dedicated CaM that is tethered to its target or as promiscuous CaM, which
Disclosure statement
None declared.
Acknowledgments
This work was supported by National Institutes of Health (HL094476 to JJS and HL30077 and HL80101 to DMB) and the American Heart Association (grant 0830470N to JJS).
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