Profiling the array of Cav3.1 variants from the human T-type calcium channel gene CACNA1G: Alternative structures, developmental expression, and biophysical variations

Mark C. Emerick, Rebecca Stein, Robin Kunze, Megan M. McNulty, Melissa R. Regan, Dorothy A. Hanck, William S. Agnew

Research output: Contribution to journalArticle

Abstract

We describe the regulated transcriptome of CACNA1G, a human gene for T-type Cav3.1 calcium channels that is subject to extensive alternative RNA splicing. Fifteen sites of transcript variation include 2 alternative 5′-UTR promoter sites, 2 alternative 3′-UTR polyadenylation sites, and 11 sites of alternative splicing within the open reading frame. A survey of 1580 fetal and adult human brain full-length complementary DNAs reveals a family of 30 distinct transcripts, including multiple functional forms that vary in expression with development. Statistical analyses of fetal and adult transcript populations reveal patterns of linkages among intramolecular splice site configurations that change dramatically with development. A shift from nearly independent, biased splicing in fetal transcripts to strongly concerted splicing in adult transcripts suggests progressive activation of multiple "programs" of splicing regulation that reorganize molecular structures in differentiating cells. Patch-clamp studies of nine selected variants help relate splicing regulation to permutations of the gating parameters most likely to modify T-channel physiology in expressing neurons. Gating behavior reflects combinatorial interactions between variable domains so that molecular phenotype depends on ensembles of coselected domains, consistent with the observed emergence of concerted splicing during development. We conclude that the structural gene and networks of splicing regulatory factors define an integrated system for the phenotypic variation of Cav3.1 biophysics during nervous system development.

LanguageEnglish (US)
Pages320-342
Number of pages23
JournalProteins
Volume64
Issue number2
DOIs
StatePublished - Aug 1 2006

Fingerprint

T-Type Calcium Channels
Alternative Splicing
Genes
Biophysics
Polyadenylation
Gene Regulatory Networks
5' Untranslated Regions
Physiology
Clamping devices
Neurology
3' Untranslated Regions
Calcium Channels
Molecular Structure
Transcriptome
Molecular structure
Nervous System
Open Reading Frames
Neurons
Brain
Complementary DNA

Keywords

  • Alpha IG
  • Alternative RNA splicing
  • Combinatorial splicing
  • Posttranscriptional gene regulation
  • Single-gene libraries
  • Single-gene transcriptomes
  • Splice variant exon scanning
  • Splice variants
  • T channels

ASJC Scopus subject areas

  • Genetics
  • Structural Biology
  • Biochemistry

Cite this

Profiling the array of Cav3.1 variants from the human T-type calcium channel gene CACNA1G : Alternative structures, developmental expression, and biophysical variations. / Emerick, Mark C.; Stein, Rebecca; Kunze, Robin; McNulty, Megan M.; Regan, Melissa R.; Hanck, Dorothy A.; Agnew, William S.

In: Proteins, Vol. 64, No. 2, 01.08.2006, p. 320-342.

Research output: Contribution to journalArticle

Emerick, Mark C. ; Stein, Rebecca ; Kunze, Robin ; McNulty, Megan M. ; Regan, Melissa R. ; Hanck, Dorothy A. ; Agnew, William S./ Profiling the array of Cav3.1 variants from the human T-type calcium channel gene CACNA1G : Alternative structures, developmental expression, and biophysical variations. In: Proteins. 2006 ; Vol. 64, No. 2. pp. 320-342
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