The long-term down-regulation of dihydropyridine receptors by Bay K 8644 in PC12 cells.

Treatment of PC12 cells with Bay K 8644 for 12 hr or more leads to an almost 80% decrease in the subsequent ability of Bay K 8644 to stimulate the uptake of radioactive calcium into the cells. This effect is a property of the s(−)isomer of Bay K 8644; pre-treatment with the R(+)isomer, now known to be a calcium channel blocker, has the opposite effect. This treatment is specific in that is does not intergfere with the stimulation of calcium uptake by potassium, ATP, or nerve growth factor. Such treatment is accompanied by a 90% decrease in the ability of Bay K 8644 to stimulate the release of norepinephrine. The characteristics of the binding of [3H]isradipine to control and to treated cells indicates that the decrease in the effect of dihydropyridines is accompanied by a marked decrease in the number of dihydropyridine binding sites with no apparent change in the affinity of the remaining sites. The continued ability of depolarizing levels of potassium to stimualte calcium uptake and the induction of the protooncogene c-fos in Bay K 8644-treated cells indicates that the L-type calcium channels are still intact, but are simply unresponsive to dihydropyridine agonists. © 1994 Wiley-Liss, Inc.1