ArticleNaunyn-Schmiedeberg's archives of pharmacology2012
Voltage-dependent open-channel block of G protein-gated inward-rectifying K(+) (GIRK) current in rat atrial myocytes by tamoxifen.
Article in Naunyn-Schmiedeberg's archives of pharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
2 citing papers in PubMed, 4 citations in OpenAlex.
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tamoxifen (Tmx) is a nonsteroidal selective estrogen receptor antagonist and is frequently used in the treatment and prevention of breast cancer. The compound and its metabolites have been reported to inhibit functions of different classes of membrane proteins, including various ion channels. For members of the inward-rectifying K(+) (Kir) channel family, interference of Tmx with binding of phosphatidylinositol 4,5-bisphosphate (PIP(2)) has been suggested as the mechanism underlying such inhibition. We have studied the inhibition of G protein-activated K(+) (GIRK) current by Tmx in isolated myocytes from hearts of adult rats using whole-cell voltage clamp and experimental conditions for measuring K(+) currents as inward currents (E (K) -50 mV; holding potential -90 mV). Extracellular Tmx reversibly inhibited GIRK current activated by acetylcholine (I (K(ACh))) with an EC(50) of 7.4 × 10(-7) M. This inhibition was composed of two components, a basal reduction in peak current and a block that required opening of channels by ACh. The open-channel block was partially relieved by depolarizing voltage steps in a voltage- and time-dependent fashion. A voltage-dependent open-channel block was not observed when I (K(ACh)) was measured as outward current (E (K) -90 mV; holding potential -40 mV). Intracellular application of Tmx via the patch clamp pipette at a concentration (7 × 10(-6) M) that caused a rapid inhibition of I (K(ACh)) upon extracellular application did not affect the current. Intracellular application of the H(2)O-soluble PIP(2) analog diC(8)-PIP(2) reduced the voltage-independent component of inhibition but had no effect on voltage-dependent open-channel block. The effects of 4-hydroxy-Tmx, a major active metabolite, tested at 2 × 10(-6) M, had effects on I (K(ACh)) analogous to those of Tmx. Inhibition of constitutive inward-rectifying K(+) current (I (K1)) in ventricular myocytes, carried by Kir2 complexes, by Tmx was devoid of a voltage-dependent component. This study suggests the voltage-dependent open-channel block of GIRK inward current as a novel mechanism of Tmx action.
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