Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0848283 (rundown)
 502 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ca2+-activated K+ channels (K(Ca2+)) constitute key regulators of the endothelial cell electrophysiological response to InsP3-mobilizing agonists. Inside-out and outside-out patch clamp experiments were thus undertaken to determine if the gating properties of a voltage-insensitive K(Ca2+) channel of intermediate conductance present in bovine aortic endothelial (BAE) cells could be modified by specific sulfhydryl (SH) oxidative and/or reducing reagents. The results obtained first indicate that cytosolic application of hydrophilic oxidative reagents such as 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB) (0.2 to 5 mM) or [(O-carboxyphenyl)thio]ethyl mercury sodium salt (thimerosal) (0.5 to 5 mM) reduces gradually the K(Ca2+) channel activity with no modification of the channel unitary conductance. The inhibitory action of DTNB (1 to 5 mM) or thimerosal (1 to 5 mM) was not reserved following withdrawal of the oxidative agents, but channel activity could partly be restored by the addition of the SH group reducing agents dithiothreitol (DTT) (5 mM) or reduced glutathione (GSH) (5 mM) in 53% and 50% of the inside-out experiments performed with DTNB and thimerosal respectively. Similar results were obtained using H2O2 at concentrations ranging from 500 microM to 10 mm as oxidative reagent. In contrast, the lipid soluble oxidative agent 4,4'-dithiodipyridine (4-PDS) (1 mM) appeared in inside-out experiments less potent than DTNB and thimerosal at inhibiting the K(Ca2+) channel activity, suggesting that the critical SH groups involved in channel gating are localized at the inner face of the cell membrane. This conclusion was further substantiated by a series of outside-out patch clamp experiments which showed that DTNB (5 mM) and thimerosal (5 mM) were unable to inhibit the K(Ca2+) channel activity when applied to the external surface of the excised membrane. Finally, no significant changes of the gating properties of the K(Ca2+) channel were observed in inside-out experiments where the SH group reducing agents DTT and GSH were applied immediately following membrane excision. However, the application of either GSH or DTT was found to partly restore channel activity in experiments where the K(Ca2+) channels showed significant rundown.
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PMID:Effects of thiol-modifying agents on a K(Ca2+) channel of intermediate conductance in bovine aortic endothelial cells. 923 92

Rundown of ionic gradients is a central feature of white matter anoxic injury; however, little is known about the contribution of anions such as Cl-. We used the in vitro rat optic nerve to study the role of aberrant Cl- transport in anoxia/ischemia. After 30 min of anoxia (NaN3, 2 mm), axonal membrane potential (V(m)) decreased to 42 +/- 11% of control and to 73 +/- 11% in the presence of tetrodotoxin (TTX) (1 microm). TTX + 4,4'-diisothiocyanatostilbene-2,2' disulfonic acid disodium salt (500 microm), a broad spectrum anion transport blocker, abolished anoxic depolarization (95 +/- 8%). Inhibition of the K-Cl cotransporter (KCC) (furosemide 100 microm) together with TTX was also more effective than TTX alone (84 +/- 14%). The compound action potential (CAP) area recovered to 26 +/- 6% of control after 1 hr anoxia. KCC blockade (10 microm furosemide) improved outcome (40 +/- 4%), and TTX (100 nm) was even more effective (74 +/- 12%). In contrast, the Cl- channel blocker niflumic acid (50 microm) worsened injury (6 +/- 1%). Coapplication of TTX (100 nm) + furosemide (10 microm) was more effective than either agent alone (91 +/- 9%). Furosemide was also very effective at normalizing the shape of the CAPs. The KCC3a isoform was localized to astrocytes. KCC3 and weaker KCC3a was detected in myelin of larger axons. KCC2 was seen in oligodendrocytes and within axon cylinders. Cl- gradients contribute to resting optic nerve membrane potential, and transporter and channel-mediated Cl- fluxes during anoxia contribute to injury, possibly because of cellular volume changes and disruption of axo-glial integrity, leading to propagation failure and distortion of fiber conduction velocities.
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PMID:Aberrant chloride transport contributes to anoxic/ischemic white matter injury. 1273 53

K(+) channels in the renal proximal tubule play an important role in salt reabsorption. Cells of the frog proximal tubule demonstrate an inwardly rectifying, ATP-sensitive K(+) conductance that is inhibited by Ba(2+), G(Ba). In this paper we have investigated the importance of phosphorylation state on the activity of G(Ba) in whole-cell patches. In the absence of ATP, G(Ba) decreased over time; this fall in G(Ba) involved phosphorylation, as rundown was inhibited by alkaline phosphatase and was accelerated by the phosphatase inhibitor F(-)(10 mM: ). Activation of PKC using the phorbol ester PMA accelerated rundown via a mechanism that was dependent on phosphorylation. In contrast, the inactive phorbol ester PDC slowed rundown. Inclusion of the PKC inhibitor PKC-ps in the pipette inhibited rundown. These data indicate that PKC-mediated phosphorylation promotes channel rundown. Rundown was prevented by the inclusion of PIP-2 in the pipette. PIP-2 also abrogated the PMA-mediated increase in rundown, suggesting that regulation of G(Ba) by PIP-2 occurred downstream of PKC-mediated phosphorylation. G-protein activation inhibited G(Ba), with initial currents markedly reduced in the presence of GTPgammas. These properties are consistent with G(Ba) being a member of the ATP-sensitive K(+) channel family.
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PMID:Phosphorylation regulates an inwardly rectifying ATP-sensitive K(+)- conductance in proximal tubule cells of frog kidney. 1655 Apr 87

The aim of the present work is to investigate a putative junction transmission [nitric oxide (NO) and ATP] in the human colon and to characterize the electrophysiological and mechanical responses that might explain different functions from both neurotransmitters. Muscle bath and microelectrode techniques were performed on human colonic circular muscle strips. The NO donor sodium nitroprusside (10 microM), but not the P2Y receptor agonist adenosine 5'-O-2-thiodiphosphate (10 microM), was able to cause a sustained relaxation. NG-nitro-L-arginine (L-NNA) (1 mM), a NO synthase inhibitor, but not 2'-deoxy-N6-methyl adenosine 3',5'-diphosphate tetraammonium salt (MRS 2179) (10 microM), a P2Y antagonist, increased spontaneous motility. Electrical field stimulation (EFS) at 1 Hz caused fast inhibitory junction potentials (fIJPs) and a relaxation sensitive to MRS 2179 (10 microM). EFS at higher frequencies (5 Hz) showed biphasic IJP with fast hyperpolarization sensitive to MRS 2179 followed by sustained hyperpolarization sensitive to L-NNA; both drugs were needed to fully block the EFS relaxation at 2 and 5 Hz. Two consecutive single pulses induced MRS 2179-sensitive fIJPs that showed a rundown. The rundown mechanism was not dependent on the degree of hyperpolarization and was present after incubation with L-NNA (1 mM), hexamethonium (100 microM), MRS 2179 (1 microM), and NF023 (10 microM). We concluded that single pulses elicit ATP release from enteric motor neurons that cause a fIJP and a transient relaxation that is difficult to maintain over time; also, NO is released at higher frequencies causing a sustained hyperpolarization and relaxation. These differences might be responsible for complementary mechanisms of relaxation being phasic (ATP) and tonic (NO).
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PMID:Purinergic and nitrergic junction potential in the human colon. 1859 88

Hyperprostaglandin E syndrome/antenatal Bartter syndrome (HPS/aBS) is a severe salt-losing renal tubular disorder and results from the mutation of renal outer medullary K(+) (ROMK1) channels. The aberrant ROMK1 function induces alterations in intracellular pH (pH(i)) gating under physiological conditions. We investigate the role of protein kinase A (PKA) in the pH(i) gating of ROMK1 channels. Using giant patch clamp with Xenopus oocytes expressing wild-type and mutant ROMK1 channels, PKA-mediated phosphorylation decreased the sensitivity of ROMK1 channels to pH(i). A homology model of ROMK1 reveals that a PKA phosphorylation site (S219) is spatially juxtaposed to the phosphatidylinositol 4,5-bisphosphate (PIP(2)) binding residues (R188, R217, and K218). Molecular dynamics simulations suggest a stable transition state, in which the shortening of distance between S219 and R217 and the movement of K218 towards the membrane after the PKA-phosphorylation can be observed. Such conformational change may bring the PIP(2) binding residues (K218) more accessible to the membrane-bound PIP(2). In addition, PIP(2) dose-dependently reactivates the acidification-induced rundown channels only when ROMK1 channels have been phosphorylated by PKA. This implies a sequence regulatory episode reflecting the role of PIP(2) in the pH(i) gating of ROMK1 channels by PKA-mediated phosphorylation. Our results provide new insights into the molecular mechanisms underlying the ROMK1 channel regulation associated with HPS/aBS.
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PMID:Functional and structural characterization of PKA-mediated pHi gating of ROMK1 channels. 1862 Aug 82