The mycotoxin paxilline inhibits the cerebellar inositol 1,4,5-trisphosphate receptor

Longland, Clare L.; Dyer, Jeanette L.; Michelangeli, Francesco

doi:10.1016/s0014-2999(00)00775-5

Cited by 28 publications

(14 citation statements)

References 21 publications

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“…1F, Table 2) and epi ⌬G t (Ϫ1.32 Ϯ 0.40 mS/cm 2 , n ϭ 5, P ϭ 0.014) consistent with a contribution of K Ca 1.1 to producing electrogenic K ϩ secretion. Paxilline at concentrations above 1.0 M also can inhibit Ca 2ϩ ATPase and the inositol 1,4,5-trisphosphate receptor (4,43). The extent of paxilline action on K Ca 1.1 was examined by restricting addition to the mucosal bathing solution and focusing on the early portion of the epinephrine response to obviate nonspecific actions.…”

Section: Resultsmentioning

confidence: 99%

Role of the BK channel (K_Ca1.1) during activation of electrogenic K⁺ secretion in guinea pig distal colon

Zhang

Halm

2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Secretagogues acting at a variety of receptor types activate electrogenic K(+) secretion in guinea pig distal colon, often accompanied by Cl(-) secretion. Distinct blockers of K(Ca)1.1 (BK, Kcnma1), iberiotoxin (IbTx), and paxilline inhibited the negative short-circuit current (I(sc)) associated with K(+) secretion. Mucosal addition of IbTx inhibited epinephrine-activated I(sc) ((epi)I(sc)) and transepithelial conductance ((epi)G(t)) consistent with K(+) secretion occurring via apical membrane K(Ca)1.1. The concentration dependence of IbTx inhibition of (epi)I(sc) yielded an IC(50) of 193 nM, with a maximal inhibition of 51%. Similarly, IbTx inhibited (epi)G(t) with an IC(50) of 220 nM and maximal inhibition of 48%. Mucosally added paxilline (10 μM) inhibited (epi)I(sc) and (epi)G(t) by ∼50%. IbTx and paxilline also inhibited I(sc) activated by mucosal ATP, supporting apical K(Ca)1.1 as a requirement for this K(+) secretagogue. Responses to IbTx and paxilline indicated that a component of K(+) secretion occurred during activation of Cl(-) secretion by prostaglandin-E(2) and cholinergic stimulation. Analysis of K(Ca)1.1α mRNA expression in distal colonic epithelial cells indicated the presence of the ZERO splice variant and three splice variants for the COOH terminus. The presence of the regulatory β-subunits K(Ca)β1 and K(Ca)β4 also was demonstrated. Immunolocalization supported the presence of K(Ca)1.1α in apical and basolateral membranes of surface and crypt cells. Together these results support a cellular mechanism for electrogenic K(+) secretion involving apical membrane K(Ca)1.1 during activation by several secretagogue types, but the observed K(+) secretion likely required the activity of additional K(+) channel types in the apical membrane.

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Section: Resultsmentioning

confidence: 99%

Role of the BK channel (K_Ca1.1) during activation of electrogenic K⁺ secretion in guinea pig distal colon

Zhang

Halm

2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Because BK channels are usually closed in unstimulated cells, the missing effect of 100 nM Ibtx and 5 M paxilline on migration are not surprising. Whereas direct effects of Ibtx different from its BK channel block are not known, paxilline has been reported to inhibit inositol 1,4,5-trisphosphate (InsP 3 ) receptors [13]. However, using 5 M paxilline, a possible block of InsP 3 receptors linked with a reduction of intracellular Ca 2+ release seems not to play a role in glioma cell migration.…”

Section: Discussionmentioning

confidence: 99%

BK channel openers inhibit migration of human glioma cells

Kraft

Krause

Jung

et al. 2003

Pflugers Arch - Eur J Physiol

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Large-conductance Ca(2+)-activated K(+) channels (BK channels) are highly expressed in human glioma cells. However, less is known about their biological function in these cells. We used the patch-clamp technique to investigate activation properties of BK channels and time-lapse microscopy to evaluate the role of BK channel activation in migration of 1321N1 human glioma cells. In whole cells, internal perfusion with a solution containing 500 nM free Ca(2+) and external application of the BK channel opener phloretin (100 micro M) shifted the activation threshold of BK channel currents toward more negative voltages of about -30 mV, which is close to the resting potential of the cells. The concentration of intracellular Ca(2+) in fura-2-loaded 1321N1 cells was measured to be 235+/-19 nM and was increased to 472+/-25 nM after treatment with phloretin. Phloretin and another BK channel opener NS1619 (100 micro M) reduced the migration velocity by about 50%. A similar reduction was observed following muscarinic stimulation of glioma cells with acetylcholine (100 micro M). The effects of phloretin, NS1619 and acetylcholine on cell migration were completely abolished by co-application of the specific BK channel blockers paxilline (5 micro M) and iberiotoxin (100 nM). The phloretin-induced increase in intracellular Ca(2+) was unaffected by the removal of extracellular Ca(2+) and co-application of paxilline. These findings indicate that glioma cell migration was inhibited through BK channel activation, independent of intracellular Ca(2+).

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“…K Ca channels have the biophysical characteristics of single-channel conductance of ϳ250 pS in symmetrical K ϩ (12,30). Each K Ca channel is composed of a pore-forming ␣-subunit and an auxiliary ␤-subunit that has modulatory functions on the channel's opening as well as sensitivity to channelblocking agents (12,28,29,43). The cytoprotective effects of K Ca channel opening were not fully recognized until very recently.…”

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confidence: 99%

“…Drugs. NS-1619, which is a selective opener of K Ca channels (32), and paxilline, a blocker of KCa channels (28,36), were purchased from BIOMOL Research Laboratories (Plymouth Meeting, PA). Both drugs were dissolved in DMSO (Sigma-Aldrich) for either coronary infusion or intraperitoneal administration (final DMSO concentration, Ͻ1%).…”

mentioning

confidence: 99%

Opening of Ca²⁺-activated K⁺ channels triggers early and delayed preconditioning against I/R injury independent of NOS in mice

Wang¹,

Yin²,

Xi³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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Opening of Ca2+-activated K+ (KCa) channels has been shown to confer early cardioprotection. It is unknown whether the opening of these channels also induces delayed cardioprotection. In addition, we determined the involvement of nitric oxide synthases (NOSs), which have been implicated in cardioprotection induced by opening of mitochondrial ATP-sensitive K+ (KATP) channels. Adult male ICR mice were pretreated with the KCa-channel opener NS-1619 either 10 min or 24 h before 30 min of global ischemia and 60 min of reperfusion (I/R) in Langendorff mode. Infusion of NS-1619 (10 μM) for 10 min before I/R led to smaller infarct sizes as compared with the vehicle (DMSO)-treated group ( P < 0.05). This infarct-limiting effect of NS-1619 was associated with improvement in ventricular functional recovery after I/R. The NS-1619-induced protection was abolished by coadministration with the KCa-channel blocker paxilline (1 μM). Similarly, pretreatment with NS-1619 (1 mg/kg ip) induced delayed protection 24 h later ( P < 0.05). Interestingly, the NS-1619-induced late protection was not blocked by the NOS inhibitor Nω-nitro-l-arginine methyl ester (15 mg/kg ip). Unlike diazoxide (the opener of mitochondrial KATP channels), NS-1619 did not increase the expression of inducible or endothelial NOS. Western blot analysis demonstrated the existence of α- and β-subunits of KCa channels in mouse heart tissue. We conclude that opening of KCa channels leads to both early and delayed preconditioning effects through a mechanism that is independent of nitric oxide.

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The mycotoxin paxilline inhibits the cerebellar inositol 1,4,5-trisphosphate receptor

Cited by 28 publications

References 21 publications

Role of the BK channel (K_Ca1.1) during activation of electrogenic K⁺ secretion in guinea pig distal colon

Role of the BK channel (K_Ca1.1) during activation of electrogenic K⁺ secretion in guinea pig distal colon

BK channel openers inhibit migration of human glioma cells

Opening of Ca²⁺-activated K⁺ channels triggers early and delayed preconditioning against I/R injury independent of NOS in mice

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The mycotoxin paxilline inhibits the cerebellar inositol 1,4,5-trisphosphate receptor

Cited by 28 publications

References 21 publications

Role of the BK channel (KCa1.1) during activation of electrogenic K+ secretion in guinea pig distal colon

Role of the BK channel (KCa1.1) during activation of electrogenic K+ secretion in guinea pig distal colon

BK channel openers inhibit migration of human glioma cells

Opening of Ca2+-activated K+ channels triggers early and delayed preconditioning against I/R injury independent of NOS in mice

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Role of the BK channel (K_Ca1.1) during activation of electrogenic K⁺ secretion in guinea pig distal colon

Role of the BK channel (K_Ca1.1) during activation of electrogenic K⁺ secretion in guinea pig distal colon

Opening of Ca²⁺-activated K⁺ channels triggers early and delayed preconditioning against I/R injury independent of NOS in mice