Key result
BAY-k 8644 fails to elicit skeletal SR Ca2+ release but inhibits the pump at high concentrations.
Why the study?
The sensitivity of sarcoplasmic reticulum Ca2+ release channels to BAY-k 8644 and potential subcellular heterogeneity among Ca2+ channels regarding drug-receptor sites was unclear.
BAY-k 8644 does not affect SR Ca2+ release channels but inhibits the SR Ca2+ pump at high concentrations, highlighting subcellular heterogeneity among Ca2+ channels.
Answers are grounded in this paper and cite their sources.
SR Ca2+ channel insensitivity to BAY-k 8644 supports subcellular heterogeneity; leaves open relevance to cardiac drug targeting.
BAY-k 8644, a nifedipine analogue, promotes Ca2+ influx into excitable cells via plasma membrane voltage-sensitive Ca2+ channels. We report here that sarcoplasmic reticulum (SR) Ca2+ release channels are insensitive to BAY-k 8644, as studied in highly purified isolated fractions and in chemically skinned fibers of rabbit skeletal muscle. This result suggests that a subcellular heterogeneity exists among Ca2+ channels, at least with respect to drug-receptor sites. In the course of this study, however we found that BAY-k 8644 reversibly inhibits the SR Ca2+ pump, i.e., it decreases Ca2+ influx into the SR lumen, although at concentrations (IC50 = 3-5 X 10(-5) M) much higher than those effective on voltage-sensitive Ca2+ channels.
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Zorzato et al. (1985) studied this question. BAY-k 8644 was evaluated on Ca2+ release from sarcoplasmic reticulum. BAY-k 8644 does not elicit Ca2+ release from skeletal muscle sarcoplasmic reticulum but reversibly inhibits the SR Ca2+ pump at high concentrations (IC50 = 3-5 X 10(-5) M).
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