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The Journal of Neuroscience, November 1, 2002, 22(21):9331-9339

Alternative Splicing of a ₄ Subunit Proline-Rich Motif Regulates Voltage-Dependent Gating and Toxin Block of Ca_v2.1 Ca²⁺ Channels

Thomas D. Helton¹, Douglas J. Kojetin², John Cavanagh², and William A. Horne¹

Departments of ¹ Molecular Biomedical Sciences and ² Molecular and Structural Biochemistry, North Carolina State University, Raleigh, North Carolina 27606

Ca²⁺ channel  subunits modify ₁ 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 ₄ subunit had ₁ 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 -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 _4b 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 ~30% made possible the building of _4a and _4b three-dimensional structural models using PSD-95 as the target sequence. The models (1) reveal that alternative splicing of the ₄ N terminus results in dramatic differences in surface charge distribution and (2) localize the proline-rich motif of _4b 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 _4a versus _4b in the human CNS. Whereas _4a is distributed throughout evolutionarily older regions of the CNS, _4b is concentrated heavily in the forebrain. These results raise interesting questions about the functional role that alternative splicing of the ₄ subunit has played in the evolution of complex neural networks.

Key words: calcium channel; ₄ subunit; PSD-95; alternative splicing; gating; N terminus; -CTx-MVIIC

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22219331-09$05.00/0

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