Mechanisms intrinsic to 5-HT2B receptor-induced potentiation of NMDA receptor responses in frog motoneurones
| Autor: | Alice M, Holohean, John C, Hackman |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Serotonin
Indoles N-Methylaspartate Nifedipine Pyridines Tetrodotoxin Receptors N-Methyl-D-Aspartate Membrane Potentials GTP-Binding Proteins Memantine 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine Receptor Serotonin 5-HT2B Animals Magnesium Gallopamil Enzyme Inhibitors Ergolines Protein Kinase C Motor Neurons Guanylyl Imidodiphosphate Sulfonamides Dose-Response Relationship Drug Rana pipiens Drug Synergism Calcium Channel Blockers Staurosporine Serotonin Receptor Agonists Spinal Cord Calcium-Calmodulin-Dependent Protein Kinases Papers Serotonin 5-HT2 Receptor Antagonists Calcium Serotonin Antagonists Dizocilpine Maleate Excitatory Amino Acid Antagonists Serotonin 5-HT2 Receptor Agonists |
| Zdroj: | British journal of pharmacology. 143(3) |
| ISSN: | 0007-1188 |
| Popis: | In the presence of NMDA receptor open-channel blockers [Mg(2+); (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801); 1-amino-3,5-dimethyladamantane (memantine)] and TTX, high concentrations (30-100 microm) of either 5-hydroxytryptamine (5-HT) or alpha-methyl-5-hydroxytryptamine (alpha-Me-5-HT) significantly potentiated NMDA-induced depolarizations of frog spinal cord motoneurones. Potentiation was blocked by LY-53,857 (10-30 microm), SB 206553 (10 microm), and SB 204741 (30 microm), but not by spiroxatrine (10 microm), WAY 100,635 (1-30 microm), ketanserin (10 microm), RS 102221 (10 microm), or RS 39604 (10-20 microm). Therefore, alpha-Me-5-HT's facilitatory effects appear to involve 5-HT(2B) receptors. These effects were G-protein dependent as they were prevented by prior treatment with guanylyl-5'-imidodiphosphate (GMP-PNP, 100 microm) and H-Arg-Pro-Lys-Pro-Gln-Gln-D-Trp-Phe-D-Trp-D-Trp-Met-NH(2) (GP antagonist 2A, 3-6 microm), but not by pertussis toxin (PTX, 3-6 ng ml(-1), 48 h preincubation). This potentiation was not reduced by protein kinase C inhibition with staurosporine (2.0 microm), U73122 (10 microm) or N-(2-aminoethyl)-5-isoquinolinesulfonamide HCl (H9) (77 microm) or by intracellular Ca(2+) depletion with thapsigargin (0.1 microm) (which inhibits Ca(2+)/ATPase). Exposure of the spinal cord to the L-type Ca(2+) channel blockers nifedipine (10 microm), KN-62 (5 microm) or gallopamil (100 microm) eliminated alpha-Me-5-HT's effects. The calmodulin antagonist N-(6-aminohexyl)-5-chloro-1-naphtalenesulfonamide (W7) (100 microm) diminished the potentiation. However, the calcium/calmodulin-dependent protein kinase II (CaM Kinase II) blocker KN-93 (10 microm) did not block the 5-HT enhancement of the NMDA responses. In summary, activation of 5-HT(2B) receptors by alpha-Me-5-HT facilitates NMDA-depolarizations of frog motoneurones via a G-protein, a rise in [Ca(2+)](i) from the entry of extracellular Ca(2+) through L-type Ca(2+) channels, the binding of Ca(2+) to calmodulin and a lessening of the Mg(2+) -produced open-channel block of the NMDA receptor. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text