Inhibition of the liver cell receptor-activated Ca²⁺ inflow system by metal ion inhibitors of voltage-operated Ca²⁺ channels but not by other inhibitors of Ca²⁺ inflow

The properties of the receptor-activated Ca²⁺ inflow system in the liver cell plasma membrane were compared with those of voltage-operated Ca²⁺ channels and receptor-operated Ca²⁺ channels present in other cell types by testing the susceptibility of the Ca²⁺ inflow system to inhibition by other metal ions and known inhibitors of Ca²⁺ movement across membranes. Co²⁺ inhibited Ca²⁺ inflow through the receptor-activated Ca²⁺ inflow system, as assessed by measurement of (a) the activation by extracellular Ca²⁺ (Ca_o²⁺) of glycogen phosphorylase in the presence of vasopressin and (b) ⁴⁵Ca²⁺ exchange in the presence of the hormone. The concentration of Co²⁺ which gave half-maximal inhibition was 280 μM. The inhibition by Co²⁺ was reversed by high Ca_o²⁺. Co²⁺ did not inhibit basal Ca²⁺ inflow as measured by ⁴⁵Ca²⁺ exchange in the absence of vasopressin. Zn²⁺, Cd²⁺, Ni²⁺ and Mn²⁺ each inhibited Ca²⁺ inflow through the receptor-activated Ca²⁺ 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 Ca²⁺ inflow was observed in the presence of Sr²⁺ or Ba²⁺. However, substantial amounts of ⁹⁰Sr²⁺ were taken up by hepatocytes. Rates of ⁹⁰Sr²⁺ uptake increased from 0.5-8 nmol per min per mg wet wt. when the extracellular concentration of Sr²⁺ was varied from 0.25 to 2.5 mM. Sr²⁺ uptake was inhibited 50% by Ca_o²⁺ with half-maximal inhibition at 100 μM Ca_o²⁺, but was not inhibited by verapamil and was not stimulated by vasopressin. The movement of Ca²⁺ through the receptor-activated Ca²⁺ inflow system was not inhibited by high concentrations of each of a number of inhibitors of voltage-operated and receptor-operated Ca²⁺ channels and intracellular Ca²⁺ movement. It is concluded that while the susceptibility to inhibition by metal ions of the receptor-activated Ca²⁺ inflow system in the liver cell plasma membrane is similar to that of voltage-operated Ca²⁺ channels, there are significant differences between the liver cell receptor-activated Ca²⁺ inflow system and both voltage-operated Ca²⁺ channels and some other receptor-operated Ca²⁺ channels with respect to inhibition by organic compounds.