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Alternative splicing of a beta4 subunit proline-rich motif regulates voltage-dependent gating and toxin block of Ca(v)2.1 Ca2+ channels

Academic Article
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Overview

authors

  • Helton, T. D.
  • Kojetin, Douglas
  • Cavanagh, J.
  • Horne, W. A.

publication date

  • 2002

journal

  • Journal of Neuroscience  Journal

abstract

  • Ca2+ channel beta subunits modify alpha1 subunit gating properties through direct interactions with intracellular linker domains. In a previous report (Helton and Horne, 2002), we showed that alternative splicing of the beta4 subunit had alpha1 subunit subtype-specific effects on Ca2+ channel activation and fast inactivation. We extend these findings in the present report to include effects on slow inactivation and block by the peptide toxin omega-conotoxin (CTx)-MVIIC. N-terminal deletion and site-directed mutagenesis experiments revealed that the effects of alternative splicing on toxin block and all aspects of gating could be attributed to a proline-rich motif found within N-terminal beta4b amino acids 10-20. Interestingly, this motif is conserved within the third postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1 domain of the distantly related membrane-associated guanylate kinase homolog, PSD-95. Sequence identity of approximately 30% made possible the building of beta4a and beta4b three-dimensional structural models using PSD-95 as the target sequence. The models (1) reveal that alternative splicing of the beta4 N terminus results in dramatic differences in surface charge distribution and (2) localize the proline-rich motif of beta4b to an extended arm structure that flanks what would be the equivalent of a highly modified PSD-95 carboxylate binding loop. Northern blot analysis revealed a markedly different pattern of distribution for beta4a versus beta4b in the human CNS. Whereas beta4a is distributed throughout evolutionarily older regions of the CNS, beta4b is concentrated heavily in the forebrain. These results raise interesting questions about the functional role that alternative splicing of the beta4 subunit has played in the evolution of complex neural networks.

subject areas

  • Alternative Splicing
  • Amino Acid Motifs
  • Animals
  • Brain
  • Calcium Channel Blockers
  • Calcium Channels, N-Type
  • Humans
  • Ion Channel Gating
  • Membrane Potentials
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Nerve Tissue Proteins
  • Oocytes
  • Organ Specificity
  • Patch-Clamp Techniques
  • Protein Structure, Tertiary
  • Protein Subunits
  • RNA, Messenger
  • Sequence Deletion
  • Sequence Homology, Amino Acid
  • Spinal Cord
  • Structure-Activity Relationship
  • Xenopus laevis
  • omega-Conotoxins
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Identity

International Standard Serial Number (ISSN)

  • 0270-6474

PubMed ID

  • 12417658
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Additional Document Info

start page

  • 9331

end page

  • 9339

volume

  • 22

issue

  • 21

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