The Modulatory Effect of Spermine on the Glutamate‐NMDA Receptor is Regionally Variable in Normal Human Adult Cerebral Cortex

Abstract

Abstruct:The MK-801, glutamate and polyamine binding sites on the N-methy1-D-aspartate class of glutamate receptors labelled with [3H]MK-801 were characterized in four cortical areas (sensorimotor, superior temporal, mid-frontal and occipital) from seven human adult control cases. Age, post-mortern delay, tissue storage time and sex had no significant effects on any of the parameters measured. Dissociation constants (K, values) for MK-801 showed similar mean values in the four cortical areas. whereas receptor densities (B,,, values) showed significant differences between sensorimotor or occipital and superior temporal or mid-frontal cortex. There were marked regional differences in the profiles of the spermine-and glutamate-increniented enhancement of specific [3H]MK-801 binding. The ECSo for the glutamate enhancement was significantly higher in the occipital than in the mid-frontal and sensorimotor cortex. whereas maximal glutamate- The N-methybaspartate (NMDA) class of ionotropic glutamate receptors plays a central role in excitatory neurotransmission in the central nervous system (Monaghan et a/. 1989). Glutamate-NMDA receptors are found on many synapses, and are important in synaptic plasticity, epilepsy, neuronal death and antinociception (Choi 1988;Bliss & Collingridge 1993; Luger et d. 1995). The receptor channel complex is composed of five different subunits permutated from the eight N R I splice variants and four NR2 subunit isoform proteins (Durand et al. 1993;Zukin & Bennett 1995;Blahos & Wenthold 1996). In vitro expression studies have shown that receptor complexes of differing subunit composition possess distinct pharmacological and physiological properties (Katsuwada et al. 1992; Monyer et ul. 1992;Wafford et al. 1993;Laube et al. 1998), which may derive from the conformational responsiveness of the receptor or the configuration of ligand sites. The receptor complex contains a number of distinct recognition sites for a range of ligands (Williams et al. 199 I), which if stimulated in combination can result in complex pharmacological responses. This complexity of structure and pharmacology makes it likely that glutamate-NMDA receptors would show variability between individuals. The goal of these studies was to characterize the pharmacology of glutamate-NMDA receptor sites for MKAuthor for correspondence: Peter R. Dodd. Department of Biochemistry, University of Queensland, Brisbane 4072, Australia (fax +61 73 365 4699. e-mail peterD@biosci.uq.edu.au). 80 1 (Dizocilpine), glutamate and spermhe in four cortical areas from normal human cases. Materials and MethodsCuse niuteriul. Brain tissue was collected at autopsy. A full postrizorterii examination was carried out on each case by an anatomical pathologist and the cause of death determined. Informed written consent was obtained from the next of kin for each of the autopsies, which were performed at Brisbane hospitals. Ethical clearance was obtained from each hospital ethics committee, and is current at Royal Brisbane Hospital under Protocol 1992122. All...

Polyamines in cell growth and cell death: molecular mechanisms and therapeutic applications

“…The effect of polyamines on other ligand-receptor systems has also been demonstrated. Polyamines alter the binding of ligands to excitatory amino acid receptors, namely N-methyl-D-aspartate (NMDA) receptors [133][134][135]. The binding of MK801, an antagonist of the NMDA receptor, was increased in the presence of polyamines.…”

“…Spermine and spermidine produced biphasic dose-response curves for binding in rat brain membrane NMDA receptor, with low concentrations ( B 100 microM) enhancing [ 125 I]-MK-801 binding and higher concentrations ( \ 100 microM) inhibiting the binding. Furthermore, the polyamine binding sites of NMDA receptor were heterogeneous in human cerebral cortex, and show a high degree of regional and individual variability, reflecting differences in ion channel activity [135]. Consequences of polyamine function at these neural cell receptors may include an analgesic effect due to polyamine deprivation [136].…”

Role of Glutamatergic and GABAergic Systems in Alcoholism

“…In situ hybridization and immunocytochemical studies have shown that NMDA receptor subunits show a high degree of regional and individual variability with some regions showing a strong preference for a particular subunit [64, 104,153]. The NR1 subunits are found in the majority of central neurons.…”

Neuronal and Glial Responses to Polyamines in the Ischemic Brain

“…By contrast, extracellular spermine has multiple effects at the NMDA subtype of glutamate receptors, including stimulation leading to increases in the size of NMDA receptor currents and voltage-dependent block (Williams et al, 1994;Zhang et al, 1994;Williams, 1997;Dingledine et al, 1999). Polyamines also alter the binding of different ligands to NMDA receptors (Williams et al, 1989;Sharma and Reynolds, 1999;Mortensen et al, 1999). The binding of dizocilpine (MK-801), an antagonist of the NMDA receptor, is increased in the presence of polyamines.…”

“…Both spermine and spermidine produce biphasic dose-response curves for binding in rat brain membrane NMDA receptor, with enhancing [ 125 I]MK-801 binding at low concentrations of below 100 µM, and inhibiting the binding at high concentrations of above 100 µM. Furthermore, the polyamine binding sites on NMDA receptor channels are heterogeneous in human cerebral cortex, with a high degree of regional and individual variability, reflecting differences in ion channel activities (Mortensen et al, 1999).…”