Mechanism of calcium gating in small-conductance calcium-activated potassium channels

Xia, Xuefeng; Fakler, Bernd; Rivard, Andre F.; Wayman, Gary A.; Johnson‐Pais, Teresa L.; Keen, J.M.; Ishii, Takahiro; Hirschberg, Birgit; Bond, Chris T.; Lutsenko, Svetlana; Maylie, James; Adelman, John P.

doi:10.1038/26758

Cited by 806 publications

(809 citation statements)

References 27 publications

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“…Similar to other studies [31,87,99], the square voltage protocols we used in the second set of experiments had a duration of 200 ms, which may be considered inadequate for SK activation. However, SK channels are voltage insensitive [17,77,78], and in neurons these channels are typically activated by Ca 2+ influx during actions potentials, which are of much shorter duration.…”

Section: Discussionmentioning

confidence: 98%

Opposing effects of spinal nerve ligation on calcium-activated potassium currents in axotomized and adjacent mammalian primary afferent neurons

Sarantopoulos¹,

McCallum²,

Rigaud³

et al. 2007

Brain Research

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Calcium-activated potassium channels regulate AHP and excitability in neurons. Since we have previously shown that axotomy decreases I Ca in DRG neurons, we investigated the association between I Ca and K (Ca) currents in control medium-sized (30-39 μM) neurons, as well as axotomized L5 or adjacent L4 DRG neurons from hyperalgesic rats following L5 SNL. Currents in response to AP waveform voltage commands were recorded first in Tyrode's solution and sequentially after: 1) blocking Na + current with NMDG and TTX; 2) addition of K (Ca) blockers with a combination of apamin 1μM, iberiotoxin 200 nM, and clotrimazole 500 nM; 3) blocking remaining K + current with the addition of 4-AP, TEA-Cl, and glibenclamide; and 4) blocking I Ca with cadmium. In separate experiments, currents were evoked (HP −60 mV, 200 ms square command pulses from −100 to +50 mV) while ensuring high levels of activation of I K(Ca) by clamping cytosolic Ca 2+ concentration with pipette solution in which Ca 2+ was buffered to1μM. This revealed I K(Ca) with components sensitive to apamin, clotrimazole and iberiotoxin. SNL decreases total I K(Ca) in axotomized (L5) neurons, but increases total I K(Ca) in adjacent (L4) DRG neurons. All I K(Ca) subtypes are decreased by axotomy, but iberiotoxin-sensitive and clotrimazole-sensitive current densities are increased in adjacent L4 neurons after SNL. In an additional set of experiments we found that small sized control DRG neurons also expressed iberiotoxin-sensitive currents, which are reduced in both axotomized (L5) and adjacent (L4) neurons.Conclusions: Axotomy decreases I K(Ca) due to a direct effect on K (Ca) channels. Axotomy-induced loss of I Ca may further potentiate current reduction. This reduction in I K(Ca) may contribute to elevated excitability after axotomy. Adjacent neurons (L4 after SNL) exhibit increased I K(Ca) current.

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Section: Discussionmentioning

confidence: 98%

Opposing effects of spinal nerve ligation on calcium-activated potassium currents in axotomized and adjacent mammalian primary afferent neurons

Sarantopoulos¹,

McCallum²,

Rigaud³

et al. 2007

Brain Research

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“…1EBIO, a surprisingly simple benzoimidazolone ( CaM leads to opening of the SK channel [88]. This opening in turn leads to reduced activation potential and vasodilatation.…”

Section: Ebiomentioning

confidence: 99%

Stabilization of protein–protein interactions by small molecules

Giordanetto¹,

Schäfer

Ottmann

2014

Drug Discovery Today

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“…Due to the lack of specificity of commonly used, membrane-permeable CaM inhibitors such as the naphthalene sulfonamide derivatives W7 and W13, trifluoperazine, and calmidazolium (Sengupta et al, 2007), we investigated the role of CaM in 5-HT 2C receptor-mediated ERK1,2 signaling by transfecting cells with a Ca 2ϩ -insensitive CaM mutant, in which aspartate residues in the first Ca 2ϩ ligand position of all four EF hand motifs of CaM have been mutated into alanine (CaM 1,2,3,4 ) (Xia et al, 1998). CaM 1,2,3,4 did not interact with the 5-HT 2C receptor C-terminus in vitro, consistent with the Ca 2ϩ -dependent nature of CaM binding to 1-10 motif ( Figure 3A, line 5), whereas wild-type GFP-CaM associated with the receptor C-terminus ( Figure 3A, line 6).…”

Section: Physical Interaction Ofmentioning

confidence: 99%

Physical Interaction of Calmodulin with the 5-Hydroxytryptamine_2C Receptor C-Terminus Is Essential for G Protein-independent, Arrestin-dependent Receptor Signaling

Labasque

Reiter

Bécamel

et al. 2008

MBoC

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The serotonin (5-hydroxytryptamine; 5-HT) 2C receptor is a G protein-coupled receptor (GPCR) exclusively expressed in CNS that has been implicated in numerous brain disorders, including anxio-depressive states. Like many GPCRs, 5-HT 2C receptors physically interact with a variety of intracellular proteins in addition to G proteins. Here, we show that calmodulin (CaM) binds to a prototypic Ca 2؉ -dependent "1-10" CaM-binding motif located in the proximal region of the 5-HT 2C receptor C-terminus upon receptor activation by 5-HT. Mutation of this motif inhibited both ␤-arrestin recruitment by 5-HT 2C receptor and receptor-operated extracellular signal-regulated kinase (ERK) 1,2 signaling in human embryonic kidney-293 cells, which was independent of G proteins and dependent on ␤-arrestins. A similar inhibition was observed in cells expressing a dominant-negative CaM or depleted of CaM by RNA interference. Expression of the CaM mutant also prevented receptor-mediated ERK1,2 phosphorylation in cultured cortical neurons and choroid plexus epithelial cells that endogenously express 5-HT 2C receptors. Collectively, these findings demonstrate that physical interaction of CaM with recombinant and native 5-HT 2C receptors is critical for G protein-independent, arrestindependent receptor signaling. This signaling pathway might be involved in neurogenesis induced by chronic treatment with 5-HT 2C receptor agonists and their antidepressant-like activity. INTRODUCTIONSerotonin (5-hydroxytryptamine; 5-HT) 2C receptors still raise particular interest in view of their broad physiological role and implication in the actions of numerous psychoactive drugs (Giorgetti and Tecott, 2004;Millan, 2005Millan, , 2006. They play an essential role in the regulation of mood and alteration of their functional status has been involved in the etiology of anxio-depressive states. 5-HT 2C receptors are themselves the target of various classes of antidepressants, including tricyclics, specific serotonin reuptake inhibitors, and "atypical" antidepressants such as mianserin, mirtazapine, and agomelatine, which behave as neutral antagonists (or inverse agonists) at 5-HT 2C receptors (Millan, 2005;Chanrion et al., 2008). Antidepressant properties of 5-HT 2C antagonists have largely been attributed to activation of dopaminergic and adrenergic pathways innervating corticolimbic structures, which exert a favorable influence upon mood and are tonically inhibited, via activation of GABAergic interneurons, by 5-HT 2C receptors.In spite of the inhibitory influence of 5-HT 2C receptors on dopaminergic and adrenergic projections, 5-HT 2C receptor agonists have shown unequivocal effectiveness in certain models of antidepressant activity (Moreau et al., 1996;Cryan and Lucki, 2000). One possible explanation for this paradoxical antidepressant action would be their positive influence on neurogenesis, a phenomenon possibly involved in therapeutic effects of antidepressant agents (Malberg et al., 2000;Santarelli et al., 2003). Activation of extracellular signalre...

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Mechanism of calcium gating in small-conductance calcium-activated potassium channels

Cited by 806 publications

References 27 publications

Opposing effects of spinal nerve ligation on calcium-activated potassium currents in axotomized and adjacent mammalian primary afferent neurons

Opposing effects of spinal nerve ligation on calcium-activated potassium currents in axotomized and adjacent mammalian primary afferent neurons

Stabilization of protein–protein interactions by small molecules

Physical Interaction of Calmodulin with the 5-Hydroxytryptamine_2C Receptor C-Terminus Is Essential for G Protein-independent, Arrestin-dependent Receptor Signaling

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Mechanism of calcium gating in small-conductance calcium-activated potassium channels

Cited by 806 publications

References 27 publications

Opposing effects of spinal nerve ligation on calcium-activated potassium currents in axotomized and adjacent mammalian primary afferent neurons

Opposing effects of spinal nerve ligation on calcium-activated potassium currents in axotomized and adjacent mammalian primary afferent neurons

Stabilization of protein–protein interactions by small molecules

Physical Interaction of Calmodulin with the 5-Hydroxytryptamine2C Receptor C-Terminus Is Essential for G Protein-independent, Arrestin-dependent Receptor Signaling

Contact Info

Product

Resources

About

Physical Interaction of Calmodulin with the 5-Hydroxytryptamine_2C Receptor C-Terminus Is Essential for G Protein-independent, Arrestin-dependent Receptor Signaling