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. 2004 Oct;143(3):351-60.
doi: 10.1038/sj.bjp.0705935. Epub 2004 Aug 31.

Mechanisms intrinsic to 5-HT2B receptor-induced potentiation of NMDA receptor responses in frog motoneurones

Alice M Holohean  1 , John C Hackman
Affiliations

Mechanisms intrinsic to 5-HT2B receptor-induced potentiation of NMDA receptor responses in frog motoneurones

Alice M Holohean et al. Br J Pharmacol. 2004 Oct.

Abstract

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.

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Figures

Figure 1
Figure 1
5-HT potentiates NMDA-evoked motoneurone depolarizations in Ringer's solution containing. Mg2+. (a) Applications of NMDA (100 μM, 10 s) in nominally Mg2+ -free Ringer's solution before and after exposure to 5-HT (30 μM, 5 min). The traces show changes in frog motoneurone membrane potential (electronically conducted along the IXth VR). In these, and in all subsequent records, negativity is indicated by an upward pen deflection and signifies a depolarization of motoneurones whose axons exit from the cord in the IXth VR. (b) The same experiment carried out in another spinal cord in Ringer's solution containing 1.0 mM Mg2+ showing facilitation produced by 5-HT and by α-Me-5-HT (30 μM, 5 min). Both experiments were performed in Ringer's solution containing TTX (0.783 μM). Applications of NMDA (100 μM, 10 s) are indicated by arrows below the baseline. Note that in this and subsequent figures, the baselines in presence of 5-HT or α-Me-5-HT have been readjusted to the control baseline in order to facilitate the observation of changes in the NMDA responses.
Figure 2
Figure 2
α-Me-5-HT-induced potentiation of NMDA responses in spinal cords exposed to NMDA receptor channel blockers. (a) Spinal cord exposed to MK-801 (6 μM, 15 min). (b) Spinal cord exposed to memantine (MEM, 10 μM, 15 min). Both experiments were performed in Ringer's solution containing TTX (0.783 μM). Applications of NMDA (100 μM, 10 s) are indicated by arrows below the baseline. Calibration bars apply to both (a and b).
Figure 3
Figure 3
Potentiating effect of α-Me-5-HT on NMDA responses is unaffected by exposure to pertussis toxin, but is blocked by GP antagonist 2A. (a) Spinal cord incubated with PTX (6 ng ml−1) for 48 h at 4°C. (b) Spinal cord exposed to GP antagonist 2A (GP-2A) (6 μM, 30 min). Applications of NMDA (100 μM, 10 s) are indicated by arrows below the baseline. Calibration bars apply to both (a and b).
Figure 4
Figure 4
Nifedipine and gallopomil block the potentiating effect of α-Me-5-HT on NMDA responses but thapsigargin does not. (a) Application of thapsigargin (THAP, 0.1 μM, 30 min). (b) Application of nifedipine (NIFED, 10 μM, 30 min). (c) Application of gallopimal (GALL, 100 μM, 30 min). Applications of NMDA (100 μM, 10 s) are indicated by arrows below the baseline.
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