Kinase and phosphatase activities intimately associated with a reconstituted calcium-dependent potassium channel

Reinhart, P. H.; Levitan, Irwin B.

doi:10.1523/jneurosci.15-06-04572.1995

Cited by 126 publications

(91 citation statements)

References 28 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%

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%

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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“…Dephosphorylation of presumably Ser 1151 , by pretreating inside-out patches from TSMCs with ATP-free solution in the presence of the PKC pseudosubstrate inhibitor PKC [19][20][21][22][23][24][25][26][27][28][29][30][31] , resulted in a switch of channel regulation from PKG to PKA, resembling the switch in the S 1151 A mutant. The regulation of BK channels by closely associated phosphatases has been shown before (16)(17)(18). Therefore, the switch of channel regulation from PKG to PKA was likely due to the activity of a phosphatase that had dephosphorylated the channel at the PKC motif before the channel became responsive to PKA.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, we wondered whether the effect of CCh on BK channel activity can be mimicked by the inhibition of channel-associated protein phosphatases (16)(17)(18). When we superfused inside-out patches from TSMCs with 20 nM of the protein phosphatase 1 inhibitor peptide (PPI2) for 5 min, NP o decreased by ∼50% at all (Fig.…”

Section: Pkc-dependent Inhibition Of Bk Channels In Tracheal Smooth Mmentioning

confidence: 99%

Dual role of protein kinase C on BK channel regulation

Zhou

Wulfsen

Utku

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

100

105

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Large conductance voltage-and Ca 2+ -activated potassium channels (BK channels) are important feedback regulators in excitable cells and are potently regulated by protein kinases. The present study reveals a dual role of protein kinase C (PKC) on BK channel regulation. Phosphorylation of S 695 by PKC, located between the two regulators of K + conductance (RCK1/2) domains, inhibits BK channel open-state probability. This PKC-dependent inhibition depends on a preceding phosphorylation of S 1151 in the C terminus of the channel α-subunit. Phosphorylation of only one α-subunit at S 1151 and S 695 within the tetrameric pore is sufficient to inhibit BK channel activity. We further detected that protein phosphatase 1 is associated with the channel, constantly counteracting phosphorylation of S 695 . PKC phosphorylation at S 1151 also influences stimulation of BK channel activity by protein kinase G (PKG) and protein kinase A (PKA). Though the S 1151 A mutant channel is activated by PKA only, the phosphorylation of S 1151 by PKC renders the channel responsive to activation by PKG but prevents activation by PKA. Phosphorylation of S 695 by PKC or introducing a phosphomimetic aspartate at this position (S 695 D) renders BK channels insensitive to the stimulatory effect of PKG or PKA. Therefore, our findings suggest a very dynamic regulation of the channel by the local PKC activity. It is shown that this complex regulation is not only effective in recombinant channels but also in native BK channels from tracheal smooth muscle.phosphorylation | protein kinase A | protein kinase G | protein phosphatase 1 | tracheal smooth muscle cells L arge conductance Ca 2+ -activated potassium channels (BK channels) are unique in their regulation by both intracellular Ca 2+ and membrane voltage. They are expressed in many tissues, and are particularly abundant in nerve and smooth muscle, where they play a key role as negative and positive feedback regulators of cell excitability by conducting repolarizing and hyperpolarizing outward currents, as has been impressively demonstrated in mice with targeted deletion of the pore-forming α-subunit (1-5). Alternative splicing of premRNA and protein phoshorylation generates structural and functional diversity of BK channels. Several serine/ threonine kinases, such as the cAMP-(PKA)-and cGMPdependent protein kinase (PKG) and protein kinase C (PKC), potently regulate BK channel activity. Their phosphorylation sites at the pore-forming α-subunit are fully conserved in almost all mammalian alternative splice variants, and mutation of the PKA and PKG phosphorylation sites abolished the kinase effect on channel activity in heterologous expression systems (6-10). In smooth muscle, PKA and PKG predominantly activate BK channels by increasing the apparent voltage and Ca 2+ sensitivity of the channel, whereas PKC exerts opposite effects (11). Experimental evidence indicates that hormones and drugs that activate PKA or PKG contribute to smooth muscle relaxation by activation of BK channels. In contrast, activ...

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“…When phosphatase activity was inhibited by microcystin, the mean current passed through the K-ATP channel in a single inside-out patch was approximately doubled. It is reported that microcystin can also enhance the modulation of K-Ca channel activity by ATP (Reinhart and Levitan 1995).…”

Section: Neurochannelmentioning

confidence: 99%

A review of neurotoxicity of microcystins

Chen

Fan

et al. 2016

Environ Sci Pollut Res

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Cyanobacterial blooms-produced microcystins are secondary metabolites which can accumulate in the food chain and contaminate water, thus posing a potential threat to the health of aquatic animals and even humans. Microcystin toxicity affects not only the liver but also the other organs, i.e., the brain. The serious neurotoxicity effects caused by microcystins then lead to various symptoms. This review focuses on the neurotoxicity of microcystins. Microcystins can cross bloodbrain barrier with the transport of Oatps/OATPs, causing neurostructural, functional, and behavioral changes. In this review, potential uptake mechanisms and neurotoxicity mechanisms are summarized, including neurotransmissions, neurochannels, signal transduction, oxidative stress, and cytoskeleton disruption. However, further researches are needed for detailed studies on signaling pathways and the downstream pathways of neurotoxicity of microcystins.

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Kinase and phosphatase activities intimately associated with a reconstituted calcium-dependent potassium channel

Cited by 126 publications

References 28 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

Dual role of protein kinase C on BK channel regulation

A review of neurotoxicity of microcystins

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