Phenylglycines can Evoke Quisqualate‐primed Depolarizations in Rat Cingulate Cortex: An Effect Associated with [³H]DL‐AP₄ Uptake

Abstract

Depolarization could be evoked in slices of rat cingulate cortex by the normally non-excitatory compound L-2-amino-4-phosphonobutyrate (L-AP4) if the slices had been sensitized by exposure to quisqualate. The magnitude of the response to L-AP4 was dependent on the concentrations of both L-AP4 and quisqualate and was inhibited by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antagonism. A series of phenylglycine analogues were capable of evoking similar dose-dependent depolarizations in the rat cingulate cortex following quisqualate sensitization, the most potent being (S)-4-carboxy-3-hydroxyphenylglycine. If the superfusate collected during application of (S)-4-carboxy-3-hydroxyphenylglycine to a quisqualate-sensitized slice was administered to a slice not previously exposed to quisqualate, a small depolarization was obtained. All the compounds shown to be capable of evoking the quisqualate-sensitized response showed affinity for the L-AP4 uptake site whilst having no affinity at ionotropic glutamate receptors and different profiles of activity at metabotropic glutamate receptors. None of the compounds was active at the metabotropic glutamate 4a receptor. There was a statistically significant correlation between a compound's effectiveness in inhibiting [3H]DL-AP4 uptake into rat cortical synaptosomes and its potency in evoking quisqualate-sensitized depolarization. It is concluded that this response may be the result of hetero-exchange between L-AP4 ligands and quisqualate.

Autoradiographic visualization of group III metabotropic glutamate receptors using [3H]‐L‐2‐amino‐4‐phosphonobutyrate

“…(SITS) and L‐cystine) or Na + ‐dependent glutamate uptake (L‐(trans)‐pyrrolidine‐2,4‐dicarboxylate) were observed. Furthermore, quisqualate is a potent inhibitor of [ 3 H]‐L‐AP4 uptake (IC 50 = 0.5 μM) (Butcher et al , 1983; Sheardown & Thomsen, 1996) and its activity at displacing [ 3 H]‐L‐AP4 binding to rat brain sections (38% at 300 μM) is therefore more in agreement with labelling of group III mGluRs (EC 50 =129 μM) (Kristensen et al , 1993) than inhibition of [ 3 H]‐l‐AP4 uptake. Agonists of ionotropic glutamate receptors (AMPA, kainate and NMDA) and antagonists of group I and II mGluRs ((S)‐4‐carboxy‐3‐hydroxyphenylglycine and (+)‐α‐methyl‐4‐carboxyphenylglycine) were also ineffective displa‐cers of [ 3 H]‐l‐AP4 binding (Table 1).…”

“…In the present study, similar compounds showed a rank order of affinity of: L‐AP4 > L‐glutamate > > quisqualate > > L‐cystine/L‐α‐aminoadipate. Furthermore, (S)‐4‐carboxy‐3‐hydroxyphenylglycine has been shown to be a very potent inhibitor of [ 3 H]‐L‐AP4‐uptake into rat cortical membranes (Sheardown & Thomsen, 1996), but did not displace [ 3 H]‐l‐AP4 binding to rat brain sections in concentrations up to 1 mM, In contrast, the rank order of affinity of mGluR ligands for [ 3 H]‐L‐AP4 binding to rat brain sections was identical to that of [ 3 H]‐L‐AP4 binding to membranes from BHK cells expressing mGluR4a (L‐AP4 > L‐SOP > L‐glutamate > L‐MAP4>(1S,3R)‐ACPD > quisqualate) (Eriksen & Thomsen, 1995; Thomsen et al , 1997). Another distinction between [ 3 H]‐L‐AP4 uptake into brain membranes and [ 3 H]‐L‐AP4 autoradiography is that GTP‐γ‐S decreased binding to brain sections (Figure 2), but did not affect uptake kinetics (data not shown).…”

Potentiation by DL‐α‐aminopimelate of the inhibitory action of a novel mGluR agonist (L‐F2CCG‐I) on monosynaptic excitation in the rat spinal cord

“…Thus, it seems unlikely that there is direct relationship between receptor selectivity and the potentiation of the inhibition of the DR‐VRP monosynaptic component. To elucidate the mechanism underlying the potentiation of the DR‐VRP monosynaptic component by DL‐α‐aminopimelate, previous studies on quisqualate priming (Robinson et al , 1986; Koerner & Johnson, 1992; Price et al , 1994; Sheardown & Thomsen, 1996) may be of use. DL‐α‐Aminopimelate, and both cis ‐ and trans ‐MCG‐I augmented depolarizing responses to quisqualate in a concentration‐dependent manner, but the latter two compounds did not cause any detectable depolarization per se even at high concentrations, in contrast to DL‐α‐aminopimelate (Ishida et al , 1995).…”