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Molecular endpoints of Ca2+/calmodulin- and voltage-dependent inactivation of Ca(v)1.3 channels.

Publication ,  Journal Article
Tadross, MR; Ben Johny, M; Yue, DT
Published in: The Journal of general physiology
March 2010

Ca(2+)/calmodulin- and voltage-dependent inactivation (CDI and VDI) comprise vital prototypes of Ca(2+) channel modulation, rich with biological consequences. Although the events initiating CDI and VDI are known, their downstream mechanisms have eluded consensus. Competing proposals include hinged-lid occlusion of channels, selectivity filter collapse, and allosteric inhibition of the activation gate. Here, novel theory predicts that perturbations of channel activation should alter inactivation in distinctive ways, depending on which hypothesis holds true. Thus, we systematically mutate the activation gate, formed by all S6 segments within Ca(V)1.3. These channels feature robust baseline CDI, and the resulting mutant library exhibits significant diversity of activation, CDI, and VDI. For CDI, a clear and previously unreported pattern emerges: activation-enhancing mutations proportionately weaken inactivation. This outcome substantiates an allosteric CDI mechanism. For VDI, the data implicate a "hinged lid-shield" mechanism, similar to a hinged-lid process, with a previously unrecognized feature. Namely, we detect a "shield" in Ca(V)1.3 channels that is specialized to repel lid closure. These findings reveal long-sought downstream mechanisms of inactivation and may furnish a framework for the understanding of Ca(2+) channelopathies involving S6 mutations.

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Published In

The Journal of general physiology

DOI

EISSN

1540-7748

ISSN

0022-1295

Publication Date

March 2010

Volume

135

Issue

3

Start / End Page

197 / 215

Related Subject Headings

  • Structure-Activity Relationship
  • Structural Homology, Protein
  • Signal Transduction
  • Rats
  • Protein Conformation
  • Point Mutation
  • Physiology
  • Molecular Sequence Data
  • Models, Structural
  • Membrane Potentials
 

Citation

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Tadross, M. R., Ben Johny, M., & Yue, D. T. (2010). Molecular endpoints of Ca2+/calmodulin- and voltage-dependent inactivation of Ca(v)1.3 channels. The Journal of General Physiology, 135(3), 197–215. https://doi.org/10.1085/jgp.200910308
Tadross, Michael R., Manu Ben Johny, and David T. Yue. “Molecular endpoints of Ca2+/calmodulin- and voltage-dependent inactivation of Ca(v)1.3 channels.The Journal of General Physiology 135, no. 3 (March 2010): 197–215. https://doi.org/10.1085/jgp.200910308.
Tadross MR, Ben Johny M, Yue DT. Molecular endpoints of Ca2+/calmodulin- and voltage-dependent inactivation of Ca(v)1.3 channels. The Journal of general physiology. 2010 Mar;135(3):197–215.
Tadross, Michael R., et al. “Molecular endpoints of Ca2+/calmodulin- and voltage-dependent inactivation of Ca(v)1.3 channels.The Journal of General Physiology, vol. 135, no. 3, Mar. 2010, pp. 197–215. Epmc, doi:10.1085/jgp.200910308.
Tadross MR, Ben Johny M, Yue DT. Molecular endpoints of Ca2+/calmodulin- and voltage-dependent inactivation of Ca(v)1.3 channels. The Journal of general physiology. 2010 Mar;135(3):197–215.

Published In

The Journal of general physiology

DOI

EISSN

1540-7748

ISSN

0022-1295

Publication Date

March 2010

Volume

135

Issue

3

Start / End Page

197 / 215

Related Subject Headings

  • Structure-Activity Relationship
  • Structural Homology, Protein
  • Signal Transduction
  • Rats
  • Protein Conformation
  • Point Mutation
  • Physiology
  • Molecular Sequence Data
  • Models, Structural
  • Membrane Potentials