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

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 Mn2+ on 5-HT1A receptor signaling complexes in rat brain and found that Mn2+ in millimolar concentration caused an increase of high-affinity agonist binding to rat hippocampal membranes in comparison with experiments in the presence of Mg2+, but not in rat cortical membranes and in Sf9 cell membranes expressing 5-HT1A receptors and Gi1 heterotrimers. Activation of G proteins with 30 μM GTPγS turned all 5-HT1A receptors in these preparations into a low-affinity state for agonist binding in the presence of 1 mM Mg2+, but not in the presence of 1 mM Mn2+ 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 Mn2+ also in cortical membranes and Sf9 cells, but not with Mg2+ or EDTA. Comparison of the abilities of GDP and GTPγS to modulate high affinity agonist binding to 5-HT1A receptors indicated that both nucleotides were almost 10-fold less potent in the presence of MnCl2 compared to MgCl2. This means that by inhibiting guanosine nucleotide binding to G proteins in complex with 5-HT1A receptors, Mn2+ acts as an enhancer for agonist binding and signal transduction. As the influence of Mn2+ 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.