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

Treatment of chromaffin cells with cyanide induced a gradual decrease in an inwardly rectifying K+ current (IIR), and washout of the mitochondrial inhibitor resulted in a rapid recovery of IIR. This diminution of IIR was reversed in a time-dependent manner by infusion of ATP or UTP, but not by that of GTP, ITP, or CTP. The restoration by ATP was not altered by addition to the pipette solution of 50 microM fluorescein 5-isothiocyanate, an inhibitor of various ATPases. A similar recovery of IIR occurred with injection of adenosine 5'-O-(3-thiotriphosphate) (ATP gamma S), but not of 5'-adenylylimidodiphosphate or alpha,beta-methyleneadenosine 5'-triphosphate. The ATP gamma S effect was biphasic, resulting in first a run-up of the current in ATP-depleted cells followed by a rundown of the current. This rundown was almost abolished by addition of guanosine 5'-O-(2-thiodiphosphate) to the ATP gamma S solution, suggesting the involvement of a G protein. Bath application of the protein kinase inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine at 100 microM, but not N-(2-[methylamino]-ethyl)-5-isoquinolinesulfonamide, induced a reversible inhibition of IIR in the presence of pipette ATP, and the inhibition was diminished by 1 microM calyculin A, a phosphatase inhibitor. Bath application of 1 microM phorbol 12,13-dibutyrate did not affect IIR. It is concluded that cyanide suppresses inward rectifier K+ channel activity via dephosphorylation and that protein kinase C, adenosine 3',5'-cyclic monophosphate-dependent kinase, or guanosine 3',5'-cyclic monophosphate-dependent kinase is not involved in modulation of the channel.
 ...
PMID:Cyanide suppression of inwardly rectifying K+ channels in guinea pig chromaffin cells involves dephosphorylation. 925 51

1. The effects of tandospirone (TDS) on dissociated rat dorsal raphe neurones were investigated using the patch-clamp method. 2. Under current-clamp conditions, TDS hyperpolarized the cell membrane, resulting in the reduction of firing rates. 3. Under voltage-clamp conditions, TDS induced an inward rectifying K+ current in a concentration-dependent manner. 4. The TDS-induced K+ currents (I(TDS)) were mimicked by 8-OH-DPAT, a 5-HT1A agonist. The I(TDS) was blocked by spiperone, a 5-HT1A receptor antagonist, in a concentration-dependent manner. 5. N-Ethylmaleimide, an agent which uncouples between the receptor and the G-protein, irreversibly blocked the I(TDS). 6. In neurones perfused intracellularly with a pipette-solution containing GTP using the conventional whole-cell patch recording, the I(TDS) showed a gradual rundown. When the neurones were perfused with GTPgammaS, TDS activated the inwardly rectifying K+ current in an irreversible manner. 7. In the inside-out patch recording mode, TDS-activated single K+ channel currents (i(TDS)) which also showed an inward rectification. When the GDP in cytosolic side was completely replaced with GTP, the open probability of i(TDS) significantly increased. 8. These results indicate that the activation of 5-HT1A receptors by TDS directly opens the inward rectifying K+ channels via a G-protein mediated process.
 ...
PMID:Tandospirone-induced K+ current in acutely dissociated rat dorsal raphe neurones. 969 74

Inwardly rectifying K+ current (IKir) in freshly isolated bovine retinal pigment epithelial (RPE) cells was studied in the whole cell recording configuration of the patch-clamp technique. When cells were dialyzed with pipette solution containing no ATP, IKir ran down completely in <10 min [half time (t1/2) = 1.9 min]. In contrast, dialysis with 2 mM ATP sustained IKir for 10 min or more. Rundown was also prevented with 4 mM GTP or ADP. When 0.5 mM ATP was used, IKir ran down by approximately 71%. Mg2+ was a critical cofactor because rundown occurred when the pipette solution contained 4 mM ATP but no Mg2+ (t1/2 = 1.8 min). IKir also ran down when the pipette solution contained 4 mM Mg2+ + 4 mM 5'-adenylylimidodiphosphate (t1/2 = 2.7 min) or 4 mM adenosine 5'-O-(3-thiotriphosphate) (t1/2 = 1.9 min), nonhydrolyzable and poorly hydrolyzable ATP analogs, respectively. We conclude that the sustained activity of IKir in bovine RPE requires intracellular MgATP and that the underlying mechanism may involve ATP hydrolysis.
 ...
PMID:ATP-dependent regulation of inwardly rectifying K+ current in bovine retinal pigment epithelial cells. 981 87

Several inwardly rectifying K+ channels show an ATP-dependent rundown of their activity. Hydrolysis of ATP is required for maintenance of channel activity. G protein-gated inwardly rectifying K+ (GIRK) channels also depend on ATP hydrolysis for gating by sodium ions or the [beta][gamma] subunits of G proteins (Sui et al. 1998). Strong evidence suggests that phosphatidylinositol 4, 5-bisphosphate (PIP2), synthesized via the hydrolysis of ATP, is absolutely required for channel gating (Sui et al. 1998; Huang et al. 1998). Interestingly, Huang and colleagues (Huang et al. 1998) showed that G[beta][gamma] subunits (the [beta][gamma] subunits of GTP-binding proteins) caused a stabilization of channel-PIP2 interactions, suggesting that G[beta][gamma] subunits may gate the channel through PIP2. Ho & Murrell-Lagnado (1999b) recently identified an aspartate residue responsible for gating these K+ channels. Ho & Murrell-Lagnado (1999a) in this issue of The Journal of Physiology present evidence that sodium ions also stabilize channel-PIP2 interactions. They suggest that Na+ effectively neutralizes a negatively charged residue, somehow promoting interactions of the channel with PIP2. These results on the mechanism of Na+ action are in close agreement with recently published work from our group. Zhang et al. (1999) showed that two C-terminal cytoplasmic arginine residues, which interact with PIP2, are localized next to the identified aspartate residue that is responsible for the Na+ effects on gating. Thus, the implication from the results of these three studies (Huang et al. 1998; Zhang et al. 1999; Ho & Murrell-Lagnado, 1999a) is that stabilization of channel-PIP2 interactions may be a common mechanism for gating GIRK channels by molecules as different as Na+ or the G[beta][gamma] subunits (see Fig. 1). These results raise many interesting questions on how modulation of channel-PIP2 interactions may lead to channel gating. Are the channel-PIP2 sites that are stabilized by G[beta][gamma] subunits shared with those that are affected by Na+? Na+ seems to act by screening the electrostatic effects that the aspartate residue exerts on the nearby PIP2-interacting arginines. How does G[beta][gamma] binding lead to stabilization of channel- PIP2 interactions? Is the Na+ sensitivity of the channel used physiologically and if so how does it relate to signalling through G proteins? Structural data for these channels and in particular for their cytoplasmic portions, which are critical for interactions with PIP2, will greatly aid our molecular understanding of the conformations needed for channel gating. Finally, although the dependence of GIRK channel activity on PIP2 is clear, it is not known yet whether the levels of PIP2 needed for channel gating are constant or under regulatory control. Answers to these and many other such questions are likely to shed light on the mechanism by which PIP2 itself serves as an important regulator of the activity of membrane proteins.
 ...
PMID:Gating of G protein-sensitive inwardly rectifying K+ channels through phosphatidylinositol 4,5-bisphosphate. 1054 32

The recombinant rat P2X(5) (rP2X(5)) receptor, a poorly understood ATP-gated ion channel, was studied under voltage-clamp conditions and compared with the better understood homomeric rP2X(1) receptor with which it may coexist in vivo. Expressed in defolliculated Xenopus laevis oocytes, rP2X(5) responded to ATP with slowly desensitizing inward currents that, for successive responses, ran down in the presence of extracellular Ca(2+) (1.8 mM). Replacement of Ca(2+) with either Ba(2+) or Mg(2+) prevented rundown, although agonist responses were very small, whereas reintroduction of Ca(2+) for short periods of time (<300 s) before and during agonist application yielded consistently larger responses. Using this Ca(2+)-pulse conditioning, rP2X(5) responded to ATP and other nucleotides (ATP, 2-methylthio-ATP, adenosine-5'-O-(thiotriphosphate), 2'-&-3'-O-(4-benzoylbenzoyl)-ATP, alpha,beta-methylene-ATP, P(1)-P((4))-diadenosine-5'-phosphate, and more) with pEC(50) values within 1 log unit of respective determinations for rP2X(1). Only GTP was selective for rP2X(5), although 60-fold less potent than ATP. At rP2X(5), lowering extracellular pH reduced the potency and efficacy of ATP, whereas extracellular Zn(2+) ions (0.1-1000 microM) potentiated then inhibited ATP responses in a concentration-dependent manner. However, these modulators affected rP2X(1) receptors in subtly different ways-with increasing H(+) and Zn(2+) ion concentrations reducing agonist potency. For P2 receptor antagonists, the potency order at rP2X(5) was pyridoxal-5-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) > 2',3'-O-(2,4,6-trinitrophenyl)ATP (TNP-ATP) > suramin > reactive blue 2 (RB-2) > diinosine pentaphosphate (Ip(5)I). In contrast, the potency order at rP2X(1) was TNP-ATP = Ip(5)I > PPADS > suramin = RB-2. Thus, the Ca(2+)-sensitized homomeric rP2X(5) receptor is similar in agonist profile to homomeric rP2X(1)-although it can be distinguished from the latter by GTP agonism, antagonist profile, and the modulatory effects of H(+) and Zn(2+) ions.
 ...
PMID:Sensitization by extracellular Ca(2+) of rat P2X(5) receptor and its pharmacological properties compared with rat P2X(1). 1223 43

Stimulation of muscarinic acetylcholine receptors (mAChRs) can activate an inward rectifier K(+) current (I(KACh)), which is mediated by the M(2) subtype of mAChR in cardiac myocytes. Recently, a novel delayed rectifier-like K(+) current mediated by activation of the cardiac M(3) receptors (designated I(KM3)) was identified, which is distinct from I(KACh) and other known K(+) currents. While I(KACh) is known to be a G(i) protein-gated K(+) channel, the signal transduction mechanisms for I(KM3) activation remained unexplored. We studied I(KM3) with whole-cell patch clamp and macropatch clamp techniques. Whole cell I(KM3) activated by choline persisted with minimal rundown over 2 h in presence of internal GTP. When GTP was replaced by guanyl-5'-yl thiophosphate, I(KM3) demonstrated rapid and extensive rundown. While I(KACh) (induced by ACh) was markedly reduced in cells pretreated with pertussis toxin, I(KM3) was unaltered. Intracellular application of antibodies targeting alpha-subunit of G(i/o) protein suppressed I(KACh) without affecting I(KM3). Antibodies targeting the N and the C terminus, respectively, of G(q) protein alpha-subunit substantially depressed I(KM3) but failed to alter I(KACh). The antibody against beta-subunits of G proteins inhibited both I(KACh) and I(KM3). I(KM3) activated by choline in the cell-attached mode of macropatches persisted in the cell-free configuration. Application of purified G(q) protein alpha-subunit or betagamma-subunit of G proteins or guanosine 5'-O-(thiotriphosphate) to the internal solution activated I(KM3)-like currents in inside-out patches. Our findings revealed a novel aspect of receptor-channel signal transduction mechanisms, and I(KM3) represents the first G(q) protein-coupled K(+) channel. We propose that the G protein-coupled K(+) channel family could be divided into two subfamilies: G(i) protein-coupled K(+) channel subfamily and G(q) protein-coupled K(+) channel subfamily.
 ...
PMID:The M3 receptor-mediated K(+) current (IKM3), a G(q) protein-coupled K(+) channel. 1514 Aug 74


<< Previous 1 2