Inhibition of the liver cell receptor-activated Ca 2+ inflow system by metal ion inhibitors of voltage-operated Ca 2+ channels but not by other inhibitors of Ca 2+ inflow

Abstract

The properties of the receptor-activated Ca 2+ inflow system in the liver cell plasma membrane were compared with those of voltage-operated Ca 2+ channels and receptor-operated Ca 2+ channels present in other cell types by testing the susceptibility of the Ca 2+ inflow system to inhibition by other metal ions and known inhibitors of Ca 2+ movement across membranes. Co 2+ inhibited Ca 2+ inflow through the receptor-activated Ca 2+ inflow system, as assessed by measurement of (a) the activation by extracellular Ca 2+ (Ca o 2+) of glycogen phosphorylase in the presence of vasopressin and (b) 45Ca 2+ exchange in the presence of the hormone. The concentration of Co 2+ which gave half-maximal inhibition was 280 μM. The inhibition by Co 2+ was reversed by high Ca o 2+. Co 2+ did not inhibit basal Ca 2+ inflow as measured by 45Ca 2+ exchange in the absence of vasopressin. Zn 2+, Cd 2+, Ni 2+ and Mn 2+ each inhibited Ca 2+ inflow through the receptor-activated Ca 2+ inflow system. The concentrations of these ions which gave half-maximal inhibition were 10, 50, 220 and 400 μM, respectively. Little inhibition of receptor-activated Ca 2+ inflow was observed in the presence of Sr 2+ or Ba 2+. However, substantial amounts of 90Sr 2+ were taken up by hepatocytes. Rates of 90Sr 2+ uptake increased from 0.5–8 nmol per min per mg wet wt. when the extracellular concentration of Sr 2+ was varied from 0.25 to 2.5 mM. Sr 2+ uptake was inhibited 50% by Ca o 2+ with half-maximal inhibition at 100 μM Ca o 2+, but was not inhibited by verapamil and was not stimulated by vasopressin. The movement of Ca 2+ through the receptor-activated Ca 2+ inflow system was not inhibited by high concentrations of each of a number of inhibitors of voltage-operated and receptor-operated Ca 2+ channels and intracellular Ca 2+ movement. It is concluded that while the susceptibility to inhibition by metal ions of the receptor-activated Ca 2+ inflow system in the liver cell plasma membrane is similar to that of voltage-operated Ca 2+ channels, there are significant differences between the liver cell receptor-activated Ca 2+ inflow system and both voltage-operated Ca 2+ channels and some other receptor-operated Ca 2+ channels with respect to inhibition by organic compounds.