Mechanisms Underlying the Activation of Large Conductance Ca2+-Activated K+ Channels by Nordihydroguaiaretic Acid

Abstract

ABSTRACT-The mechanisms underlying the activation of large conductance Ca 2+-activated K + (BK) channel by nordihydroguaiaretic acid (NDGA) were examined in human embryonic kidney (HEK293) cells, where BK channel a (BKa) or a plus b1 subunit (BKab1) was heterologously expressed, and also in freshly isolated porcine coronary arterial smooth muscle cells (PCASMCs). The activity of both BKa and BKab1 channels was increased by 10 mM NDGA in similar manners, indicating the selective action on the a subunit to increase Ca 2+ sensitivity. The application of NDGA to PCASMCs induced outward current and hyperpolarization under voltage and current clamp, respectively, in a concentration-dependent manner (³3 mM). These effects were blocked by 100 nM iberiotoxin. Electrical events induced by NDGA (³10 m M) were, unexpectedly, associated with the increase in [Ca 2+ ] i . After the treatment with caffeine and ryanodine, the [Ca 2+ ] i increase by NDGA was markedly reduced and the hyperpolarization by NDGA was attenuated. The Ca 2+ release by 10 mM NDGA was preceded by membrane depolarization of mitochondria. These results indicate that BK channel opening by NDGA in PCASMCs is due to the direct action on a subunit and also to Ca 2+ release from sarcoplasmic reticulum, presumably via, at least in part, the inhibition of mitochondria respiration.

Activation of large-conductance, Ca2+-activated K+ channels by cannabinoids

“…Regarding the voltage dependence of BK channel openers, BMS-204352 (15), 17␤-estradiol (37), and tamoxifen (9) show potentiating effects only at positive potentials. In contrast, methAEA as well as NS-1619, nordihydroguaiaretic acid (46), and pimaric acid (19) enhance BK channel current at potentials positive to Ϫ30 mV in a voltageindependent fashion. This feature of methAEA is important with respect to the regulation of resting membrane potential by BK channel activation.…”

“…A primary target of nordihydroguaiaretic acid and pimaric acid into BK channels is the BK ␣-subunit itself; the efficacy of these compounds in activating BK channel currents composed of the BK ␣-subunit alone is comparable to the activation of currents coexpressing BK ␣-and BK ␤ 1 -subunits. In addition, these BK channel openers effectively activated BK-␣ channels in the excised inside-out patch configuration (19,46), and it is likely that BMS-204352 interacts mainly with the BK ␣-subunit (15). In contrast, dehydrosoyasaponin I, 17␤-estradiol, and tamoxifen increase BK channel currents only when the BK ␣-subunit is coexpressed with BK-␤ 1 , suggesting that these compounds bind to the BK-␤ 1 subunit (9, 14, 37).…”

Involvement of Inositol 1,4,5-Trisphosphate Formation in the Voltage-Dependent Regulation of the Ca2+Concentration in Porcine Coronary Arterial Smooth Muscle Cells

“…Two-dimensional Ca 2ϩ images were obtained by using a fast scanning confocal fluorescent microscope (RCM-8000; Nikon, Tokyo, Japan) equipped with a Fluor 40ϫ, 1.15 NA objective lens (water immersion; Nikon), and Ratio3 software (Nikon) (Imaizumi et al, 1998;Yamamura et al, 2001Yamamura et al, , 2002. Freshly isolated myocytes were loaded with 100 M indo-1 (Dojin Laboratories, Kumamoto, Japan) by diffusion from the recording pipette for a few minutes.…”

Natural Modulators of Large-Conductance Calcium-Activated Potassium Channels

“…This catechol, a well-known inhibitor of lipoxygenase (that represents a key biological target for many diseases such as asthma, atherosclerosis and cancer), besides its wide range of pharmacological activities, such as antioxidant capability, also showed a BK-activator profile in single smooth muscle cells of porcine coronary artery, as investigated by some Japanese authors using the patch-clamp technique [37]. Some of the same researchers, more recently, have published two studies about its mechanism and site of action on BK channels, both of which seem to be independent of the inhibition of lipoxygenase and of antioxidant activity [38], and to directly involve the a subunit [39], respectively.…”