An interview with Douglas S. Krafte, Ph.D. Interview by Vicki P. Glaser.
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Biology↗
Biomedical subjects
Douglas S Krafte
Publications and source records attributed to Douglas S Krafte.
Decrease of inward rectification as a mechanism for arachidonic acid-induced potentiation of hKir2.3.
Previously, we showed that arachidonic acid (AA) potentiates currents flowing through a cloned human inwardly rectifying K(+) channel, hKir2.3. The mechanism by which this potentiation occurs is not understood. Here, we report that this potentiation is mediated by multiple mechanisms and that one of them, which we studied in more detail, is consistent with AA-induced decrease of inward rectification. AA (10 micro M) potentiation of hKir2.3 whole-cell current increased with depolarization (40% greater at -47 mV than at -127 mV) and decreased with elevated extracellular [K(+)] (158+/-21%, 56+/-8% and 38+/-9% in 5.4, 70 and 135 mM K(+), respectively). Hyperpolarization elicited inward currents consisting of an instantaneous and two time-dependent components with time constants (at -97 mV) of 6.4+/-1.1 ms and 27.8+/-4.1 ms, respectively. AA (10 microM) significantly decreased the slow time constant (14.1+/-0.7 ms). Consistent with the kinetic changes, AA (10 microM) right-shifted the voltage dependence of the chord conductance (mid-point shifted by +9 mV). In inside-out patches where inward rectification was minimal, AA potentiation (38+/-3%) was smaller than in whole-cell recording and was not voltage dependent. These results are consistent with the idea that AA potentiates hKir2.3 in part by decreasing inward rectification of the channel.
Animals↗
Tenidap, a novel anti-inflammatory agent, is an opener of the inwardly rectifying K+ channel hKir2.3.
We studied the effect of a novel anti-inflammatory agent, tenidap, on a cloned inwardly rectifying K+ channel, hKir2.3. Tenidap (a) potently potentiated 86Rb+ efflux through hKir2.3 channels expressed in Chinese hamster ovary cells (EC50=402 nM), (b) reversibly and dose-dependently increased whole-cell and macro-patch hKir2.3 currents (maximum whole-cell current response to tenidap was 230+/-27% of control; EC50=1.3 microM.), and (c) caused dose-dependent and Ba2+-sensitive membrane hyperpolarizations and concurrent decreases in input resistance. Potentiation of hKir2.3 by tenidap was unaffected by inhibitors of phospholipase A2, protein kinase C, or arachidonic acid metabolic pathways. The action of tenidap was not intracellular. Tenidap also had little or no effect on currents flowing through hKir2.1, Kv1.5, and micro1 Na+ channels. Our results demonstrate that tenidap is a potent opener of hKir2.3 and suggest that it can serve as a valuable pharmacological tool for studying physiological and pathological processes involving Kir2.3.
Animals↗