Action of extracellular divalent cations on native α-amino-3-hydroxy- 5-methylisoxazole-4-propionate (AMPA) receptors

The effects of divalent cations on Ca2+-impermeable containing (GluR2 subunit) MPA receptors of hippocampal pyramidal neurones isolated from rat brain was studied using patch-clamping. Ca2+, Mg2+, Mn2+, Co2+, Ni2+ and Zn2+ inhibited currents induced by kainate and glutamate. Inhibition was fast, reversible and voltage independent. The rank order of activities was Ni2+ > Zn2+ > Co2+ > Ca2+ > Mn2+ > Mg2+. Cyclothiazide (0.1 mM) significantly reduced inhibition by divalent cations and 6, 7 dinitroquinoxaline-2.3-dione (DNQX). However, high concentrations of Ni2+ and DNQX inhibited AMPA receptors even in the presence of cyclothiazide. The inhibitory effect of divalent cations as well as DNQX was counteracted by an increase in agonist concentration. In the presence of divalent cations the EC50 values of kainate and glutamate were increased, but the maximal response was not changed. An increase in agonist concentration induced a parallel shift in the concentration-inhibition curve for a divalent cation. These data suggest a competitive-like type of inhibition. However, an increase in agonist concentration reduced the inhibitory action of Ni2+ less than that of DNQX. This gave evidence against direct competition between divalent cations and AMPA receptor agonists. A 'complex-competition' hypothesis was proposed to explain the inhibitory action of divalent cations; it is suggested that divalent cations form ion-agonist complexes, which compete with free agonist for agonist-binding sites on AMPA receptors. © 2005 The Authors Journal Compilation © 2005 International Society for Neurochemistry

The Thalidomide scandal: a long road to justice

Overview: Thalidomide was an over-the-counter ‘wonder drug’, marketed to pregnant women in the 1950s and 1960s to treat morning sickness and anxiety. Lyn Rowe was born in Melbourne in 1962 with no arms and no legs after her mother took the drug during her pregnancy. In 2011, aged 49, Rowe finally won a multimillion-dollar settlement from the Australian distributor of thalidomide. It’s estimated that as many as 10,000 babies worldwide may have been born with deformities because their mothers had taken the drug. Former journalist and Lyn Rowe’s lawyer, Michael Magazanik, has written Silent Shock – a book that unpacks the incredible story of the Rowe family’s struggle against the drug companies who have sought to evade responsibility. Join Magazanik in conversation with Jill Singer for a discussion of justice delayed – and almost denied