Functional Diversity in Neuronal Voltage-Gated Calcium Channels by Alternative Splicing of Ca_vα₁

Abstract

Alternative splicing is a critical mechanism used extensively in the mammalian nervous system to increase the level of diversity that can be achieved by a set of genes. This review focuses on recent studies of voltage-gated calcium (Ca) channel Ca(v)alpha1 subunit splice isoforms in neurons. Voltage-gated Ca channels couple changes in neuronal activity to rapid changes in intracellular Ca levels that in turn regulate an astounding range of cellular processes. Only ten genes have been identified that encode Ca(v)alpha1 subunits, an insufficient number to account for the level of functional diversity among voltage-gated Ca channels. The consequences of regulated alternative splicing among the genes that comprise voltage-gated Ca channels permits specialization of channel function, optimizing Ca signaling in different regions of the brain and in different cellular compartments. Although the full extent of alternative splicing is not yet known for any of the major subtypes of voltage-gated Ca channels, it is already clear that it adds a rich layer of structural and functional diversity".

Cumulative inactivation of N-type CaV2.2 calcium channels modified by alternative splicing

“…Alternative splicing has the potential to generate a staggering number of structurally and functionally distinct classes of voltage-gated calcium channels from one Ca V ␣ 1 gene (14). Exon 18a is present in rat, mouse, and human Ca V 2.2 genes, defined by consensus splice junction ag-gt, and expressed in rat, mouse, and human tissue (A. C. Gray and D.L., unpublished observations).…”

“…Voltage-gated calcium channels are subject to extensive alternative splicing, and in several cases this leads to changes in the time course and voltage dependence of channel inactivation (14). However, the effects of alternative splicing on the ability of Ca V 2 calcium channels to respond to more physiologically relevant stimuli, including action potential waveforms, has not been assessed.…”

“…However, the effects of alternative splicing on the ability of Ca V 2 calcium channels to respond to more physiologically relevant stimuli, including action potential waveforms, has not been assessed. Furthermore, alternative splicing occurs most often in cytoplasmic regions of Ca V 2 channels (14), where effects on channel gating are hard to predict. In particular, exon 18a in the Ca V 2.2 genes of rat, mouse, and human encodes 21 aa in the cytoplasmic II-III loop.…”

“…Exon 18a modifies the voltage dependence of steady-state inactivation under certain conditions without affecting the kinetics or voltage dependence of channel activation (15). A homologous alternatively spliced exon whose expression is regulated is also present in the Ca V 2.3 gene (14,17,18). Functional studies of Ca V 2.3 channels that contain this exon indicate that it regulates the Ca sensitivity of certain channel properties (19,20).…”

Voltage-activated Calcium Currents in Octopus Cells of the Mouse Cochlear Nucleus

“…The lowvoltage-activated T-type channels are encoded by genes in the Ca V 3 family and inactivate rapidly and completely. Diversity in voltage-gated Ca 2+ channels arises not only from their being encoded by various families of genes but also because the transcripts from those genes have numerous alternatively spliced forms (Lipscombe et al 2002).…”