Mechanisms intrinsic to 5‐HT_2B receptor‐induced potentiation of NMDA receptor responses in frog motoneurones

Abstract

In the presence of NMDA receptor open‐channel blockers [Mg2+; (+)‐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 μM) of either 5‐hydroxytryptamine (5‐HT) or α‐methyl‐5‐hydroxytryptamine (α‐Me‐5‐HT) significantly potentiated NMDA‐induced depolarizations of frog spinal cord motoneurones. Potentiation was blocked by LY‐53,857 (10–30 μM), SB 206553 (10 μM), and SB 204741 (30 μM), but not by spiroxatrine (10 μM), WAY 100,635 (1–30 μM), ketanserin (10 μM), RS 102221 (10 μM), or RS 39604 (10–20 μM). Therefore, α‐Me‐5‐HT's facilitatory effects appear to involve 5‐HT2B receptors. These effects were G‐protein dependent as they were prevented by prior treatment with guanylyl‐5′‐imidodiphosphate (GMP‐PNP, 100 μM) and H‐Arg‐Pro‐Lys‐Pro‐Gln‐Gln‐D‐Trp‐Phe‐D‐Trp‐D‐Trp‐Met‐NH2 (GP antagonist 2A, 3–6 μM), 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 μM), U73122 (10 μM) or N‐(2‐aminoethyl)‐5‐isoquinolinesulfonamide HCl (H9) (77 μM) or by intracellular Ca2+ depletion with thapsigargin (0.1 μM) (which inhibits Ca2+/ATPase). Exposure of the spinal cord to the L‐type Ca2+ channel blockers nifedipine (10 μM), KN‐62 (5 μM) or gallopamil (100 μM) eliminated α‐Me‐5‐HT's effects. The calmodulin antagonist N‐(6‐aminohexyl)‐5‐chloro‐1‐naphtalenesulfonamide (W7) (100 μM) diminished the potentiation. However, the calcium/calmodulin‐dependent protein kinase II (CaM Kinase II) blocker KN‐93 (10 μM) did not block the 5‐HT enhancement of the NMDA responses. In summary, activation of 5‐HT2B receptors by α‐Me‐5‐HT facilitates NMDA‐depolarizations of frog motoneurones via a G‐protein, a rise in [Ca2+]i from the entry of extracellular Ca2+ through L‐type Ca2+ channels, the binding of Ca2+ to calmodulin and a lessening of the Mg2+ ‐produced open‐channel block of the NMDA receptor. British Journal of Pharmacology (2004) 143, 351–360. doi:

Serotonin as a Modulator of Glutamate- and GABA-Mediated Neurotransmission: Implications in Physiological Functions and in Pathology

“…At a cellular level, 5-HT is able to increase glutamateinduced excitability of spinal motoneurons [77,82,168,187]. Consistently, an experimentally-induced decrease in 5-HT levels in ventral horn was found to suppress postural muscle tone, an effect that is likely to contribute to the muscle atonia occurring during rapid eye movement (REM) sleep [98].…”

“…With respect to glutamate, 5-HT modulation is often directed to NMDA-mediated effects [61,77,80,106], whose function is related to the inhibitory control of movement [188]. Interestingly, recent studies show that impulsive-type behaviours (such as hyperlocomotion and stereotypy) induced by blockade of NMDA receptors can be attenuated by administration of 5-HT 2A antagonists [24,76], suggesting a possible use of 5-HT 2A receptor antagonists to normalise NMDA receptor hypofunction.…”

Phospholipase C Is Required for Changes in Postsynaptic Structure and Function Associated with NMDA Receptor-Dependent Long-Term Depression

“…Although NMDA receptors themselves are known to be both positively and negatively regulated by signaling pathways downstream of PLC, such as PKC, inhibition of PLC with U73122 on its own has no effect on NMDA receptor currents (Lei et al, 1999;Holohean and Hackman, 2004). Thus, U73122 inhibition of PLC is more likely preventing LTD induction by blocking signaling pathways downstream of NMDA receptors.…”

5-Hydroxytryptamine 5HT2C Receptors Form a Protein Complex with N-Methyl-d-aspartate GluN2A Subunits and Activate Phosphorylation of Src Protein to Modulate Motoneuronal Depolarization

“…Serotonin (5-hydroxytryptamine; 5HT) is a major neuromodulator of NMDA-mediated motoneuron output (12)(13)(14)(15). Spinal motoneurons express a variety of 5HT receptor subtypes (16 -20) that are activated by 5HT released from tracts descending from the raphe nuclei (21) and also by 5HT circulating extrasynaptically (22).…”