Trends in Neurosciences
Volume 36, Issue 10, October 2013, Pages 598-609
Journal home page for Trends in Neurosciences

Review
Control of neuronal voltage-gated calcium ion channels from RNA to protein

https://doi.org/10.1016/j.tins.2013.06.008Get rights and content

Highlights

  • How many different voltage-gated calcium (CaV) channels are there and should one care?

  • All mammalian Cacna1 genes have the potential to generate hundreds of CaV channels.

  • Cell specific mechanisms control CaV channel function at RNA and protein levels according to cell type.

  • Cell specific protein–protein interactions control subcellular CaV channel trafficking and function.

  • Cell specific and subcellular expression patterns of CaV isoforms are important for disease and treatment development.

Voltage-gated calcium ion (CaV) channels convert neuronal activity into rapid intracellular calcium signals to trigger a myriad of cellular responses. Their involvement in major neurological and psychiatric diseases, and importance as therapeutic targets, has propelled interest in subcellular-specific mechanisms that align CaV channel activity to specific tasks. Here, we highlight recent studies that delineate mechanisms controlling the expression of CaV channels at the level of RNA and protein. We discuss the roles of RNA editing and alternative pre-mRNA splicing in generating CaV channel isoforms with activities specific to the demands of individual cells; the roles of ubiquitination and accessory proteins in regulating CaV channel expression; and the specific binding partners that contribute to both pre- and postsynaptic CaV channel function.

Section snippets

Ten CaV genes, thousands of different CaV mRNAs, and many more functionally different proteins

…different Ca currents show so many differences in fundamental properties that we find it easier to assume that there are more than one type. [1]

CaV channels are present at every critical step of information transfer in the nervous system, from signal detection to perception, and from neuronal development to programmed apoptosis. Strategically located at points of sensory detection and on both sides of the synapse, CaV channels have a defining role in integrating signals and influencing

Cell specific alternative pre-mRNA splicing and RNA editing regulate CaV channel function

…the more you look, the more you see. (Robert M. Pirsig, 1974)

Alternative pre-mRNA splicing is particularly prevalent in the mammalian brain, and is essential for normal neuronal development, axon targeting, neuronal excitability, and neural circuit formation. This form of pre-mRNA processing occurs in the nucleus of the cell, and is controlled by the concerted actions of a set of cell specific, RNA-binding proteins called splicing factors. Trans-acting splicing factors bind to consensus cis

Mechanisms that control numbers of CaV channels at the cell surface

CaV channel activity depends not only on the pattern of expression of functionally different splice and RNA edited isoforms, but also on the overall expression level of CaV channel proteins in specific subcellular compartments. Counting CaV2 channels at active zones of different synapses by quantitative molecular and ultrastructural analyses recently demonstrated a tight correlation between presynaptic CaV2.1 and CaV2.2 channel number and vesicle release probability 30, 31, whereas the third

Synapse-specific location of CaV2 channels

CaV2.1 and CaV2.2 channels couple differentially to neurotransmitter vesicle release machinery according to synapse type. In hippocampal interneurons, CaV2.1 channels mediate the release of neurotransmitter from parvalbumin (PV)-expressing fast-spiking basket cells, whereas CaV2.2 channels mediate the release of neurotransmitter from cholecystokinin (CCK)-expressing basket cells 50, 51. The physical distance between presynaptic channels and calcium sensors of exocytosis are predicted to differ

Concluding remarks and challenges

The number of molecularly distinct CaV proteins that can be generated from CACNA1 genes is stunning. Cell specific gene expression, alternative pre-mRNA splicing, RNA editing, posttranslational modifications including ubiquitination, miRNA targeting, and subcellular specific protein–protein interactions are all used according to the demands of the cell.

At the level of RNA, we still lack cell specific information about which mRNA is expressed and when. Several cell type-specific transcriptome

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    *

    Current address: Oregon Hearing Research Center, Oregon Health & Science University, Portland, OR 97239, USA.

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