Allosteric Regulators Selectively Prevent Ca-feedback of Ca and Na Channels

Overview

Journal Elife

Specialty Biology

Date 2018 Sep 11

PMID 30198845

Citations 17

Authors

Jacqueline Niu

Ivy E Dick

WanJun Yang

Moradeke A Bamgboye

David T Yue

Gordon Tomaselli

Takanari Inoue

Manu Ben-Johny

Affiliations

Soon will be listed here.

Abstract

Calmodulin (CaM) serves as a pervasive regulatory subunit of Ca1, Ca2, and Na1 channels, exploiting a functionally conserved carboxy-tail element to afford dynamic Ca-feedback of cellular excitability in neurons and cardiomyocytes. Yet this modularity counters functional adaptability, as global changes in ambient CaM indiscriminately alter its targets. Here, we demonstrate that two structurally unrelated proteins, SH3 and cysteine-rich domain (stac) and fibroblast growth factor homologous factors (fhf) selectively diminish Ca/CaM-regulation of Ca1 and Na1 families, respectively. The two proteins operate on allosteric sites within upstream portions of respective channel carboxy-tails, distinct from the CaM-binding interface. Generalizing this mechanism, insertion of a short RxxK binding motif into Ca1.3 carboxy-tail confers synthetic switching of CaM regulation by Mona SH3 domain. Overall, our findings identify a general class of auxiliary proteins that modify Ca/CaM signaling to individual targets allowing spatial and temporal orchestration of feedback, and outline strategies for engineering Ca/CaM signaling to individual targets.

Citing Articles

Inactivation of CaV1 and CaV2 channels.

Limpitikul W, Dick I J Gen Physiol. 2025; 157(2).

PMID: 39883005 PMC: 11781272. DOI: 10.1085/jgp.202313531.

A genetically encoded actuator boosts L-type calcium channel function in diverse physiological settings.

Del Rivero Morfin P, Chavez D, Jayaraman S, Yang L, Geisler S, Kochiss A Sci Adv. 2024; 10(44):eadq3374.

PMID: 39475605 PMC: 11524184. DOI: 10.1126/sciadv.adq3374.

CACNA1C-Related Channelopathies.

Herold K, Hussey J, Dick I Handb Exp Pharmacol. 2023; 279:159-181.

PMID: 36598608 PMC: 10576998. DOI: 10.1007/164_2022_624.

Fibroblast growth factor homologous factors serve as a molecular rheostat in tuning arrhythmogenic cardiac late sodium current.

Chakouri N, Rivas S, Roybal D, Yang L, Diaz J, Hsu A Nat Cardiovasc Res. 2022; 1(5):1-13.

PMID: 35662881 PMC: 9161660. DOI: 10.1038/s44161-022-00060-6.

Molecular interactions of STAC proteins with skeletal muscle dihydropyridine receptor and excitation-contraction coupling.

Shishmarev D, Rowland E, Aditya S, Sundararaj S, Oakley A, Dulhunty A Protein Sci. 2022; 31(5):e4311.

PMID: 35481653 PMC: 9019556. DOI: 10.1002/pro.4311.

References

Hennessey J, Marcou C, Wang C, Wei E, Wang C, Tester D . FGF12 is a candidate Brugada syndrome locus. Heart Rhythm. 2013; 10(12):1886-94. PMC: 3870051. DOI: 10.1016/j.hrthm.2013.09.064. View

Brusse E, de Koning I, Maat-Kievit A, Oostra B, Heutink P, Van Swieten J . Spinocerebellar ataxia associated with a mutation in the fibroblast growth factor 14 gene (SCA27): A new phenotype. Mov Disord. 2005; 21(3):396-401. DOI: 10.1002/mds.20708. View

Venetucci L, Denegri M, Napolitano C, Priori S . Inherited calcium channelopathies in the pathophysiology of arrhythmias. Nat Rev Cardiol. 2012; 9(10):561-75. DOI: 10.1038/nrcardio.2012.93. View

Linsley J, Hsu I, Groom L, Yarotskyy V, Lavorato M, Horstick E . Congenital myopathy results from misregulation of a muscle Ca2+ channel by mutant Stac3. Proc Natl Acad Sci U S A. 2016; 114(2):E228-E236. PMC: 5240691. DOI: 10.1073/pnas.1619238114. View

Lou J, Laezza F, Gerber B, Xiao M, Yamada K, Hartmann H . Fibroblast growth factor 14 is an intracellular modulator of voltage-gated sodium channels. J Physiol. 2005; 569(Pt 1):179-93. PMC: 1464207. DOI: 10.1113/jphysiol.2005.097220. View

Coebergh J, Fransen van de Putte D, Snoeck I, Ruivenkamp C, van Haeringen A, Smit L . A new variable phenotype in spinocerebellar ataxia 27 (SCA 27) caused by a deletion in the FGF14 gene. Eur J Paediatr Neurol. 2013; 18(3):413-5. DOI: 10.1016/j.ejpn.2013.10.006. View

Mahajan A, Sato D, Shiferaw Y, Baher A, Xie L, Peralta R . Modifying L-type calcium current kinetics: consequences for cardiac excitation and arrhythmia dynamics. Biophys J. 2007; 94(2):411-23. PMC: 2157257. DOI: 10.1529/biophysj.106.98590. View

Wang H, George M, Kim J, Wang C, Pitt G . Ca2+/calmodulin regulates trafficking of Ca(V)1.2 Ca2+ channels in cultured hippocampal neurons. J Neurosci. 2007; 27(34):9086-93. PMC: 6672201. DOI: 10.1523/JNEUROSCI.1720-07.2007. View

TOMLINSON W, Stea A, Bourinet E, Charnet P, Nargeot J, Snutch T . Functional properties of a neuronal class C L-type calcium channel. Neuropharmacology. 1993; 32(11):1117-26. DOI: 10.1016/0028-3908(93)90006-o. View

10.

Linse S, Forsen S . Determinants that govern high-affinity calcium binding. Adv Second Messenger Phosphoprotein Res. 1995; 30:89-151. DOI: 10.1016/s1040-7952(05)80005-9. View

11.

Polster A, Nelson B, Olson E, Beam K . Stac3 has a direct role in skeletal muscle-type excitation-contraction coupling that is disrupted by a myopathy-causing mutation. Proc Natl Acad Sci U S A. 2016; 113(39):10986-91. PMC: 5047181. DOI: 10.1073/pnas.1612441113. View

12.

Campiglio M, Coste de Bagneaux P, Ortner N, Tuluc P, Van Petegem F, Flucher B . STAC proteins associate to the IQ domain of Ca1.2 and inhibit calcium-dependent inactivation. Proc Natl Acad Sci U S A. 2018; 115(6):1376-1381. PMC: 5819422. DOI: 10.1073/pnas.1715997115. View

13.

Ben-Johny M, Dick I, Sang L, Limpitikul W, Kang P, Niu J . Towards a Unified Theory of Calmodulin Regulation (Calmodulation) of Voltage-Gated Calcium and Sodium Channels. Curr Mol Pharmacol. 2015; 8(2):188-205. PMC: 4960983. DOI: 10.2174/1874467208666150507110359. View

14.

Wu J, Yan Z, Li Z, Qian X, Lu S, Dong M . Structure of the voltage-gated calcium channel Ca(v)1.1 at 3.6 Å resolution. Nature. 2016; 537(7619):191-196. DOI: 10.1038/nature19321. View

15.

Nanou E, Sullivan J, Scheuer T, Catterall W . Calcium sensor regulation of the CaV2.1 Ca2+ channel contributes to short-term synaptic plasticity in hippocampal neurons. Proc Natl Acad Sci U S A. 2016; 113(4):1062-7. PMC: 4743814. DOI: 10.1073/pnas.1524636113. View

16.

Kraner S, Novak K, Wang Q, Peng J, Rich M . Altered sodium channel-protein associations in critical illness myopathy. Skelet Muscle. 2012; 2(1):17. PMC: 3441911. DOI: 10.1186/2044-5040-2-17. View

17.

Haeseleer F, Sokal I, Verlinde C, Erdjument-Bromage H, Tempst P, Pronin A . Five members of a novel Ca(2+)-binding protein (CABP) subfamily with similarity to calmodulin. J Biol Chem. 2000; 275(2):1247-60. PMC: 1364469. DOI: 10.1074/jbc.275.2.1247. View

18.

Bock G, Gebhart M, Scharinger A, Jangsangthong W, Busquet P, Poggiani C . Functional properties of a newly identified C-terminal splice variant of Cav1.3 L-type Ca2+ channels. J Biol Chem. 2011; 286(49):42736-42748. PMC: 3234942. DOI: 10.1074/jbc.M111.269951. View

19.

Marshall C, Nishikawa T, Osawa M, Stathopulos P, Ikura M . Calmodulin and STIM proteins: Two major calcium sensors in the cytoplasm and endoplasmic reticulum. Biochem Biophys Res Commun. 2015; 460(1):5-21. DOI: 10.1016/j.bbrc.2015.01.106. View

20.

Goldfarb M, Schoorlemmer J, Williams A, Diwakar S, Wang Q, Huang X . Fibroblast growth factor homologous factors control neuronal excitability through modulation of voltage-gated sodium channels. Neuron. 2007; 55(3):449-63. PMC: 2974323. DOI: 10.1016/j.neuron.2007.07.006. View