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)

Activation and reactivation of the ATP-sensitive K+ channel (IK.ATP) were studied with the patch-clamp technique in guinea-pig ventricular myocytes. The K+ channel openers, nicorandil and pinacidil, activated IK.ATP in an internal ATP-dependent manner. Both drugs increased the open probability of IK.ATP without changing the channel conductance. They prolonged lifetimes of bursts and shortened interburst intervals without influencing the fast gating within bursts. These effects were the opposite of those of internal ATP. However, the interaction between ATP and either nicorandil or pinacidil appeared not to be simple competition. We found that three carbonyl compounds--3,4-dihydroxybenzaldehyde, 2,3-dihydroxybenzaldehyde, and 2,4-dihydroxyacetophenone--could activate IK.ATP through an intracellular mechanism that was dependent upon the presence of ADP and Mg2+. It has been suggested that these three carbonyl compounds bind covalently to proteins to form a Schiff base, which may be responsible for their effects upon IK.ATP. Internal application of the proteolytic enzyme trypsin prevented both the spontaneous and Ca(2+)-induced rundown of the KK.ATP channel. Tryptic digestion did not change either the channel's sensitivity to inhibition by ATP nor the fast gating kinetics of IK.ATP. Internal application of an exopeptidase, carboxypeptidase A, but not leu-aminopeptidase, prevented the spontaneous and Ca(2+)-induced rundown of the IK/ATP channel, effects similar to those of trypsin treatment. These results suggest that the target site of trypsin digestion may be located on the carboxy (C)-terminal of the channel proteins or associated regulatory units.
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PMID:Activation and reactivation of the ATP-sensitive K+ channel of the heart can be modified by drugs. 825 28

1. The adenosine 5'-triphosphate (ATP)-sensitive K+ channel current was recorded in guinea-pig ventricular myocytes using the patch clamp technique with inside-out patch configuration. Modification of the channel activity by intracellular application of an endoprotease trypsin was studied, and was related to a possible model of regulation of this channel. 2. Maximal ATP-sensitive K+ channel activity was observed immediately upon formation of inside-out patches in the ATP-free internal solution, thereafter activity declined both spontaneously and gradually with time; a phenomenon known as rundown. When trypsin (1 mg/ml) was applied to the intracellular side of the membrane upon formation of inside-out patches, spontaneous run-down did not occur, and this trypsin action was irreversible. Neither trypsin (1 mg/ml) applied with trypsin inhibitor (0.25 mg/ml) nor heat-denatured trypsin (1 mg/ml) could mimic this effect. When trypsin was applied to the patches after run-down, channels were reactivated at approximately 13 min. 3. Treatment with trypsin did not affect unitary current amplitude, channel gating kinetics, or sensitivity to intracellular ATP. 4. Intracellularly applied Ca2+ induced run-down of channel activity in a dose-dependent manner. In membrane patches that were treated with trypsin (1 mg/ml) for 20 min, intracellularly applied Ca2+ up to 1 mM did not induce run-down of channel activity. 5. Intracellular application of an exopeptidase, carboxypeptidase A (1 mg/ml), but not Leu-aminopeptidase (0.5 mg/ml), prevented spontaneous or Ca(2+)-induced run-down of channel activity. 6. As postulated for several other channels, such as Na+ and Ca2+ channels, there may be a possible 'chemical gate' that is responsible for run-down of this channel activity. Application of trypsin might somehow modify this 'chemical gate', resulting in prevention of spontaneous or Ca(2+)-induced run-down. This target site for trypsin may be situated on the carboxy-terminus of the channel proteins, or of associated regulatory units. Because ATP sensitivity remained intact after trypsin treatment, the trypsin-selective site for channel inhibition is not related physically to the ATP binding site.
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PMID:Modification of the adenosine 5'-triphosphate-sensitive K+ channel by trypsin in guinea-pig ventricular myocytes. 841 Jul 13