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 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 30μM GTPγS turned all 5-HT(1A) receptors in these preparations into a low-affinity state for agonist binding in the presence of 1mM Mg(2+), but not in the presence of 1mM Mn(2+) in rat hippocampal membranes. However, if 1μM 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.
Institute of Chemistry, University of Tartu, Ravila 14A, 50411 Tartu, Estonia.
Sven
S
Parkel
Lauri
L
Tõntson
Ago
A
Rinken
D000818:Animals; D002460:Cell Line; D006151:Guanosine / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D008345:Manganese / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000378:metabolism*; D018411:Spodoptera
D043562:Receptors, G-Protein-Coupled; D058825:Serotonin 5-HT1 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D006151:Guanosine; D008345:Manganese