Millimolar Mn2+ influences agonist binding to 5-HT1A receptors by inhibiting guanosine nucleotide binding to receptor-coupled G-proteins.

Abstract Manganese is an essential trace element but its overexposure causes poisoning (called manganism) that shares several symptoms with Parkinson's disease, but with a mechanism that is still not well understood: in addition to involvement of the dopaminergic system, both serotonergic and peptiergic systems have been implicated. In the present report we have studied the influence of Mn 2+ on 5-HT 1A receptor signaling complexes in rat brain and found that Mn 2+ in millimolar concentration caused an increase of high-affinity agonist binding to rat hippocampal membranes in comparison with experiments in the presence of Mg 2+ , but not in rat cortical membranes and in Sf9 cell membranes expressing 5-HT 1A receptors and G i1 heterotrimers. Activation of G proteins with 30 μM GTPγS turned all 5-HT 1A receptors in these preparations into a low-affinity state for agonist binding in the presence of 1 mM Mg 2+ , but not in the presence of 1 mM Mn 2+ in rat hippocampal membranes. However, if 1 μM GTPγS was used for G protein activation, a substantial amount of high affinity agonist binding was detected in the presence of Mn 2+ also in cortical membranes and Sf9 cells, but not with Mg 2+ or EDTA. Comparison of the abilities of GDP and GTPγS to modulate high affinity agonist binding to 5-HT 1A receptors indicated that both nucleotides were almost 10-fold less potent in the presence of MnCl 2 compared to MgCl 2 . This means that by inhibiting guanosine nucleotide binding to G proteins in complex with 5-HT 1A receptors, Mn 2+ acts as an enhancer for agonist binding and signal transduction. As the influence of Mn 2+ resembles the hypersensitivity of dopaminergic system in Parkinsonial models, it can be proposed that at least some symptoms of manganism are connected with a change of signal transduction complex caused by manganese-nucleotide complexes.