Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 20 (2)

The Crossroad of Ion Channels and Calmodulin in Disease

Affiliations
Review

The Crossroad of Ion Channels and Calmodulin in Disease

Janire Urrutia et al. Int J Mol Sci.

Abstract

Calmodulin (CaM) is the principal Ca2+ sensor in eukaryotic cells, orchestrating the activity of hundreds of proteins. Disease causing mutations at any of the three genes that encode identical CaM proteins lead to major cardiac dysfunction, revealing the importance in the regulation of excitability. In turn, some mutations at the CaM binding site of ion channels cause similar diseases. Here we provide a summary of the two sides of the partnership between CaM and ion channels, describing the diversity of consequences of mutations at the complementary CaM binding domains.

Keywords: calcium; calmodulin; channelopathies; ion channels.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Location of the different mutations in calmodulinopathies. Top left panel: schematic representation of the structure of CaM showing Ca2+ coordination and mutations found in calmodulinopathies. The grey areas highlight the EF-hands shown in the main panel. Disease-associated residues are colored in green (IVF: idiopathic ventricular fibrillation), blue (CPVT: catecholaminergic polymorphic ventricular tachycardia), red (LQTS: long QT syndrome) and orange (both: LQTS/BrS) in the CaM sequence. The Ca2+-binding loop of each EF-hand is emphasized with a grey background.
Figure 2
Figure 2
Topology of CaV1, NaV1, and KV7 channels. Schematic representation of CaV1 (A), NaV1 (B), and KV7 (C) channels. The functional assemblies are schematically represented on the left side. Note that CaV1 and NaV1 channels are composed of four repeats within a single polypeptide, while four subunits are needed to form KV7 channels. Homologous repeat domains (DI–DIV); transmembrane segments (S1–S6); N-terminal spatial Ca2+ transforming element (NSCaTE), CaM Binding Domain (CaMBD), IQ motif, EF-hands, TW helix, helix B, helix C, and helix D are labeled. (D) Composite 3D structures of CaV1/NaV1 channels (top panel; combining PDBs: 5GJW and 4DCK) and KV7 channels (bottom panel; PDBs: 5VMS and 3BJ4). The pore forming domain is colored in magenta, the CaM N-lobe in blue and C-lobe in green. Transparency was set to 40%, allowing the view of CaM from the top, and the pore from a lateral perspective. Note that in the presence of Ca2+, the N-lobe of CaM should be near the N-terminal of the CaV channels or the DIII–DIV linker for NaV channels after activation (not shown). The auxiliary β subunits are not shown. Pymol 1.5 was used to render panel D.
Figure 3
Figure 3
Location of the different mutations found in CaV1, NaV1, and KV7 channel CaMBD that lead to channelopathies. Left: schematic overall location of different CaMBD (red circle). Note that KV7 channels have four IQ/helix A and helix B domains (See Figure 2). NSCaTE (N-terminal spatial Ca2+ transforming element) is only present in CaV1 channels, DIII–DIV repeat domain linker CaMBD is only found in NaV1 channels, the IQ motif (IQ) is present in all of them and helix B (hB) is only present in KV7 channels. Right: The IFM inactivation motif of NaV is boxed. The interacting CaM lobe or channel domain is indicated on top of the corresponding sequences. The location of the mutation and the disease linked to each mutation is indicated in the color scheme at the bottom. BrS: Brugada syndrome; LQTS: long QT syndrome; IGE: idiopathic generalized epilepsy; GF: gingival fibromatosis; EE: epileptic encephalopathy; BFNS: benign familial neonatal seizures.

Similar articles

See all similar articles

Cited by 4 articles

References

    1. Hoeflich K.P., Ikura M. Calmodulin in action: Diversity in target recognition and activation mechanisms. Cell. 2002;108:739–742. doi: 10.1016/S0092-8674(02)00682-7. - DOI - PubMed
    1. Carafoli E., Krebs J. Why Calcium? How Calcium Became the Best Communicator. J. Biol. Chem. 2016;291:20849–20857. doi: 10.1074/jbc.R116.735894. - DOI - PMC - PubMed
    1. Cheung W.Y. Cyclic 3’,5’-nucleotide phosphodiesterase. Demonstration of an activator. Biochem. Biophys. Res. Commun. 1970;38:533–538. doi: 10.1016/0006-291X(70)90747-3. - DOI - PubMed
    1. Kakiuchi S., Yamazaki R. Calcium dependent phosphodiesterase activity and its activating factor (PAF) from brain studies on cyclic 3’,5’-nucleotide phosphodiesterase (3) Biochem. Biophys. Res. Commun. 1970;41:1104–1110. doi: 10.1016/0006-291X(70)90199-3. - DOI - PubMed
    1. Klee C.B., Crouch T.H., Richman P.G. Calmodulin. Annu. Rev. Biochem. 1980;49:489–515. doi: 10.1146/annurev.bi.49.070180.002421. - DOI - PubMed
Feedback