Aminopyridines block an inactivating potassium current having slow recovery kinetics

The blocking action of aminopyridines on an inactivating K current (lKi) in GH3 pituitary cells was studied before and after altering the macroscopic decay of the current with N-bromoacetamide (NBA). The first depolarizing pulse delivered either seconds or minutes after beginning 4-aminopyridine (4A...

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Bibliographic Details
Published in:Biophysical journal 1990-12, Vol.58 (6), p.1481-1489
Main Authors: Wagoner, P.K., Oxford, G.S.
Format: Article
Language:English
Subjects:
4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid - pharmacology
4-Aminopyridine - pharmacology
Acetamides - pharmacology
aminopyridine
Animals
Biological and medical sciences
Cell Line
Cell physiology
Fundamental and applied biological sciences. Psychology
Kinetics
Membrane and intracellular transports
Membrane Potentials - drug effects
Molecular and cellular biology
Pituitary Neoplasms
potassium
Potassium Channels - drug effects
Potassium Channels - physiology
Time Factors
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Summary:The blocking action of aminopyridines on an inactivating K current (lKi) in GH3 pituitary cells was studied before and after altering the macroscopic decay of the current with N-bromoacetamide (NBA). The first depolarizing pulse delivered either seconds or minutes after beginning 4-aminopyridine (4AP) application, elicited a current with both a more rapid decay and a reduced peak amplitude. The rapid decay (or time-dependent block) was especially prominent in NBA-treated cells. With continued drug application, subsequent test pulses revealed a stable block of peak current, greater in NBA-treated than control cells. Recovery from block was enhanced by hyperpolarizing holding potentials and by the first depolarizing pulse delivered after prolonged recovery intervals. Unlike aminopyridine block of other K currents, there was no convincing evidence for voltage shifts in activation or inactivation, or for voltage and frequency-dependent unblock. Increasing the open probability of the channels did, however, facilitate the block. Although the behavior of currents in 4AP was suggestive of "open channel block," the block was not produced by 4-aminopyridine methiodide, a positively charged aminopyridine. Moreover, because partial block and recovery occurred without opening the channels we suggest that aminopyridines bind to, or near, this K channel, that this binding is enhanced by opening the channel, and that a conformational change is induced which mimics inactivation. Because recovery from block is enhanced by negative potentials, we suggest that aminopyridine molecules may become "trapped" by inactivation awaiting the slow process of reactivation to escape their binding sites.
ISSN:0006-3495
1542-0086
DOI:10.1016/S0006-3495(90)82493-0