title: Characterization of C-terminal Splice Variants of Cav1.4 Ca2+ Channels in Human Retina.
abstract: Voltage-gated Ca(2+) channels (Cav) undergo extensive alternative splicing that greatly enhances their functional diversity in excitable cells. Here, we characterized novel splice variants of the cytoplasmic C-terminal domain of Cav1.4 Ca(2+) channels that regulate neurotransmitter release in photoreceptors in the retina. These variants lack a portion of exon 45 and/or the entire exon 47 (Cav1.4Δex p45, Cav1.4Δex 47, Cav1.4Δex p45,47) and are expressed in the retina of primates but not mice. Although the electrophysiological properties of Cav1.4Δex p45 are similar to those of full-length channels (Cav1.4FL), skipping of exon 47 dramatically alters Cav1.4 function. Deletion of exon 47 removes part of a C-terminal automodulatory domain (CTM) previously shown to suppress Ca(2+)-dependent inactivation (CDI) and to cause a positive shift in the voltage dependence of channel activation. Exon 47 is crucial for these effects of the CTM because variants lacking this exon show intense CDI and activate at more hyperpolarized voltages than Cav1.4FL The robust CDI of Cav1.4Δex 47 is suppressed by CaBP4, a regulator of Cav1.4 channels in photoreceptors. Although CaBP4 enhances activation of Cav1.4FL, Cav1.4Δex 47 shows similar voltage-dependent activation in the presence and absence of CaBP4. We conclude that exon 47 encodes structural determinants that regulate CDI and voltage-dependent activation of Cav1.4, and is necessary for modulation of channel activation by CaBP4.
authors.affiliation: From the Department of Physiology and Biophysics, University of Washington, Seattle, Washington 98195 and.
authors.forename: Françoise
authors.initials: F
authors.lastname: Haeseleer
authors.affiliation: the Departments of Molecular Physiology and Biophysics, Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, Iowa 52242.
authors.forename: Brittany
authors.initials: B
authors.lastname: Williams
authors.affiliation: the Departments of Molecular Physiology and Biophysics, Otolaryngology Head-Neck Surgery, Neurology, and amy-lee@uiowa.edu.
authors.forename: Amy
authors.initials: A
authors.lastname: Lee
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005091:Exons; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D008254:Macaca nemestrina; D051379:Mice; D012160:Retina / Q000166:cytology / Q000378:metabolism*
chemical_list: C514441:CABP4 protein, human; C113330:CACNA1F protein, human; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins
keywords: calcium channel; calcium-binding protein; electrophysiology; photoreceptor; retina