Alternative splicing of potassium channels: a dynamic switch of cellular excitability

Shipston, Michael J.

doi:10.1016/s0962-8924(01)02068-2

Cited by 99 publications

(90 citation statements)

References 19 publications

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“…In these assays we stimulated PKA activity intimately associated with the channel by applying cAMP to the intracellular face of isolated inside-out patches. As previously reported (17) the effects of cAMP in this system are dependent upon the presence of Mg-ATP, and the actions of cAMP are completely abolished by the PKA inhibitor peptide PKI [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] . Although STREX channels are inhibited whereas ZERO channels are activated by PKA closely associated with the channel (17), the short LZ1-competing peptides effectively blocked PKAdependent regulation of either splice variant.…”

Section: Pkac Docking With Mouse Bk Channel Variants Mediated Via a Lz1supporting

confidence: 80%

“…BK channels play a central role in the regulation of cellular excitability because they are activated directly by both voltage and intracellular free calcium (4 -6) and potently modulated by reversible protein phosphorylation (1). For example, they provide a dynamic link between electrical and chemical signaling events in cells, are major determinants of vascular smooth muscle tone (5,7), and regulate action potential duration and frequency as well as neurotransmitter and hormone release in neurons and endocrine cells (6,8). A single gene (KCNMA1) encodes for the pore-forming ␣-subunits of BK channels in all mammalian tissues (9).…”

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confidence: 99%

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Leucine Zipper Domain Targets cAMP-dependent Protein Kinase to Mammalian BK Channels

Tian

Coghill

MacDonald

et al. 2003

Journal of Biological Chemistry

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Large conductance, calcium-and voltage-activated potassium (BK) channels control excitability in many tissues and are regulated by several protein kinases and phosphatases that remain associated with the channels in cell-free patches of membrane. Here, we report the identification of a highly conserved, non-canonical, leucine zipper (LZ1) in the C terminus of mammalian BK channels that is required for cAMP-dependent protein kinase ( Reversible protein phosphorylation represents a fundamental cellular regulatory mechanism to control the activity and function of plasma membrane ion channels (1). The co-ordination, specificity, and compartmentalization of ion channel regulation by reversible protein phosphorylation is facilitated by assembly with signaling complexes comprising cognate protein kinases and protein phosphatases. Assembly of ion channels with signaling complexes typically results from multiple protein-protein interactions mediated by distinct interaction domains (2) allowing signaling molecules to interact directly with an ion channel or indirectly as part of a higher order complex.Large conductance calcium-and voltage-activated potassium (BK) channels have been widely exploited as models of ion channel regulation by reversible protein phosphorylation; however, the molecular basis for kinase and phosphatase assembly with the BK channel is largely unknown

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Section: Pkac Docking With Mouse Bk Channel Variants Mediated Via a Lz1supporting

confidence: 80%

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confidence: 99%

Leucine Zipper Domain Targets cAMP-dependent Protein Kinase to Mammalian BK Channels

Tian

Coghill

MacDonald

et al. 2003

Journal of Biological Chemistry

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“…The diversity in electrical properties of different cell types, or of the same cell type at different developmental stages or physiological conditions, is defined not only by expression and subunit composition of distinct ion channels, but also by posttranscriptional and posttranslational modifications of their component subunits (1,2). Alternative splicing of pre-mRNA to yield changes in primary structure and protein phosphorylation to alter folding and charge are fundamentally important mechanisms to generate structural and functional diversity of ion channel proteins (3)(4)(5)(6)(7)(8).…”

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confidence: 99%

Profiling the Phospho-status of the BKCa Channel α Subunit in Rat Brain Reveals Unexpected Patterns and Complexity

Yan

Olsen

Park

et al. 2008

Molecular & Cellular Proteomics

101

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Molecular diversity of ion channel structure and function underlies variability in electrical signaling in nerve, muscle, and non-excitable cells. Protein phosphorylation and alternative splicing of pre-mRNA are two important mechanisms to generate structural and functional diversity of ion channels. However, systematic mass spectrometric analyses of in vivo phosphorylation and splice variants of ion channels in native tissues are largely lacking. Mammalian large-conductance calcium-activated potassium (BK Ca ) channels are tetramers of ␣ subunits (BK␣) either alone or together with ␤ subunits, exhibit exceptionally large single channel conductance, and are dually activated by membrane depolarization and intracellular Ca 2؉ . The cytoplasmic C terminus of BK␣ is subjected to extensive pre-mRNA splicing and, as predicted by several algorithms, offers numerous phospho-acceptor amino acids. Here we use nanoflow liquid chromatography tandem mass spectrometry on BK Ca channels affinity-purified from rat brain to analyze in vivo BK␣ phosphorylation and splicing. We found 7 splice variations and identified as many as 30 Ser/Thr in vivo phosphorylation sites; most of which were not predicted by commonly used algorithms. Of the identified phosphosites 23 are located in the C terminus, four were found on splice insertions. Electrophysiological analyses of phosphoand dephosphomimetic mutants transiently expressed in HEK-293 cells suggest that phosphorylation of BK␣ differentially modulates the voltage-and Ca 2؉ -dependence of channel activation. These results demonstrate that the pore-forming subunit of BK Ca channels is extensively phosphorylated in the mammalian brain providing a molecular basis for the regulation of firing pattern and excitability through dynamic modification of BK␣ structure and function.

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“…BK channels are one member of this triumvirate and are overexpressed by malignant glioma cells (9)(10)(11)(12)(13)(14). BKa channels have a complex splicing pattern with multiple forms known to be expressed (21)(22)(23)(24). A novel BK isoform was genetically cloned by Liu and coworkers (25) in 2002 and was called the gBK.…”

Section: Discussionmentioning

confidence: 99%

“…Several variant BKa channels are produced via alternative splicing pathways (21)(22)(23)(24). Liu et al (25) described a novel BKa channel, which they named the glioma BK channel (gBK), because it was initially described and genetically cloned from malignant human D54 glioma cells.…”

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confidence: 99%

Glioma Big Potassium Channel Expression in Human Cancers and Possible T Cell Epitopes for Their Immunotherapy

Ge¹,

Hoa²,

Cornforth

et al. 2012

The Journal of Immunology

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Big potassium (BK) ion channels have several spliced variants. One spliced variant initially described within human glioma cells is the glioma BK (gBK) channel. This isoform consists of 34 aa inserted into the intracellular region of the basic BK ion channel. PCR primers specific for this inserted region confirmed that human glioma cell lines and freshly resected surgical tissues from glioblastoma multiforme patients strongly expressed gBK mRNA. Normal human brain tissue very weakly expressed this transcript. An Ab specific for this gBK isoform confirmed that human glioma cells displayed this protein in the cell membrane, mitochondria, Golgi, and endoplasmic reticulum. Within the gBK region, two putative epitopes (gBK1 and gBK2) are predicted to bind to the HLA-A*0201 molecule. HLA-A*0201–restricted human CTLs were generated in vitro using gBK peptide-pulsed dendritic cells. Both gBK1 and gBK2 peptide-specific CTLs killed HLA-A2+/gBK+ gliomas, but they failed to kill non-HLA-A2–expressing but gBK+ target cells in cytolytic assays. T2 cells loaded with exogenous gBK peptides, but not with the influenza M1 control peptide, were only killed by their respective CTLs. The gBK-specific CTLs also killed a variety of other HLA-A*0201+ cancer cells that possess gBK, as well as HLA-A2+ HEK cells transfected with the gBK gene. Of clinical relevance, we found that T cells derived from glioblastoma multiforme patients that were sensitized to the gBK peptide could also kill target cells expressing gBK. This study shows that peptides derived from cancer-associated ion channels maybe useful targets for T cell-mediated immunotherapy.

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Alternative splicing of potassium channels: a dynamic switch of cellular excitability

Cited by 99 publications

References 19 publications

Leucine Zipper Domain Targets cAMP-dependent Protein Kinase to Mammalian BK Channels

Leucine Zipper Domain Targets cAMP-dependent Protein Kinase to Mammalian BK Channels

Profiling the Phospho-status of the BKCa Channel α Subunit in Rat Brain Reveals Unexpected Patterns and Complexity

Glioma Big Potassium Channel Expression in Human Cancers and Possible T Cell Epitopes for Their Immunotherapy

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