Effects of lanthanides on muscarinic acetylcholine receptor function

Incubation of mouse neuroblastoma cells (clone N1E-115) with the lanthanides terbium, europium, neodymium, and lanthanum resulted in a concentration-dependent reduction in the maximal cyclic GMP response to full agonists of the muscarinic acetylcholine receptor, and an increase in the response to partial agonists. At 1 mM concentration these lanthanides also caused a significant decrease in the EC₅₀ of the agonists, which was accompanied by a significant reduction in the binding affinity of the ³H-labeled antagonist quinuclidinyl benzilate (QNB), as determined for both mouse neuroblastoma cells and rat brain homogenates. However, this concentration of the lanthanides did not cause a significant change in the agonist equilibrium dissociation constant. The rank order of potency of the lanthanides for their effects on the EC₅₀ for agonists and on the affinity of the antagonist was Tb³⁺ > Eu³⁺ > Nd³⁺ > La³⁺. Calcium ions mimicked the effects of lanthanides on the EC₅₀ but had opposite effects on maximal responses. In addition, high calcium concentrations decreased the effects of Tb³⁺ on the EC₅₀ and on [³H]QNB binding with no change in their effect on maximal cyclic GMP responses. We conclude that these lanthanides increase the efficacy of agonists, probably by interacting with Ca²⁺ binding sites on a factor which couples the receptor to the calcium channels; and that the lanthanides reduce maximal cyclic GMP responses to agonists by interacting with the calcium channels.