Calcium and pancreatic β-Cell function. IX. Demonstration of Lanthanide-Induced inhibition of insulin secretion independent of modifications in transmembrane Ca²⁺ fluxes

β-Cell-rich pancreatic islets were microdissected from noninbred ob/ob-mice and used to examine the mode of action of trivalent lanthanide ions on insulin secretion. La³⁺, Sm³⁺, and Tm³⁺ were equally effective inhibitors of basal and glucose-stimulated insulin release. As indicated by perifusion experiments with Tm³⁺, the inhibitory action was prompt, sustained, and readily reversible. Despite the similarities among the lanthanides in inhibiting insulin secretion, these cations differed considerably in their ability to impair transmembrane ⁴⁵Ca fluxes. Using 10 different members of the lanthanide series, it was possible to demonstrate that their effectiveness to inhibit ⁴⁵Ca uptake increased with ionic radius. La³⁺ markedly inhibited intracellular uptake and superficial binding of ⁴⁵Ca at both 3 and 20 mM glucose. However, Tm³⁺ failed to affect intracellular ⁴⁵Ca uptake and only reduced superficial binding of ⁴⁵Ca at 3 mM glucose. In efflux experiments, Tm³⁺ did not affect basal or glucose-stimulated ⁴⁵Ca washout from islets perifused with a medium containing 1.28 mM Ca²⁺. In a Ca²⁺-deficient medium, Tm³⁺ caused a slight transient increase, followed by reduction of ⁴⁵Ca washout. However, when glucose was omitted, there was a prompt increase in the washout of radioactivity in the presence of Tm³⁺. Accordingly, the potent inhibitory action of Tm³⁺ on insulin secretion is not matched by changes in transmembrane Ca²⁺ fluxes. Since the lanthanides do not penetrate intracellularly, we propose the existence of cationic binding sites in the β-cell plasma membrane with direct inhibitory effects on insulin secretion.