Spermine modulation of the glutamate_nmda receptor is differentially responsive to conantokins in normal and Alzheimer's disease human cerebral cortex

Abstract

The pharmacology of the N-methyl-D-aspartate (NMDA) receptor site was examined in pathologically affected and relatively spared regions of cerebral cortex tissue obtained at autopsy from Alzheimer's disease cases and matched controls. The affinity and density of the [ 3 H]MK-801 binding site were delineated along with the enhancement of [ 3 H]MK-801 binding by glutamate and spermine. Maximal enhancement induced by either ligand was regionally variable; glutamatemediated maximal enhancement was higher in controls than in Alzheimer's cases in pathologically spared regions, whereas spermine-mediated maximal enhancement was higher in controls in areas susceptible to pathological damage. These and other data suggest that the subunit composition of NMDA receptors may be locally variable. Studies with modified conantokin-G (con-G) peptides showed that Ala(7)-con-G had higher affinity than Lys(7)-con-G, and also defined two distinct binding sites in controls. Nevertheless, the affinity for Lys(7)-con-G was higher overall in Alzheimer's brain than in control brain, whereas the reverse was true for Ala(7)-con-G. Over-excitation mediated by specific NMDA receptors might contribute to localized brain damage in Alzheimer's disease. Modified conantokins are useful for identifying the NMDA receptors involved, and may have potential as protective agents.

Selective loss of NMDA receptor NR1 subunit isoforms in Alzheimer's disease

“…We have previously shown that certain conantokin peptides are weakly selective for the differing forms of NMDA receptor found in different regions of the AD brain (Ragnarsson et al 2002). Knowledge of the subunit composition should provide a convenient vehicle for further development by expressing the abundant and scarce combinations in a suitable recombinant system.…”

The Polyamine Pathway as a Potential Target for Vascular Diseases: Focus on Restenosis

“…For example, a recent interesting study revealed that polyamines are able to modulate the mRNA stability of JunD, a growth-inhibitory protein in intestinal epithelial cells, through the RNA-binding proteins HuR and AUF1, thus providing new insight into the molecular functions of cellular polyamines [17]. Moreover, polyamines are able to modulate ligand-receptor interactions and functions, including estrogen/ER [18], the nuclear receptors/vitamin D receptor-interacting proteins [19] and the glutamate/N-methyl-D-aspartate receptors [20].…”

Effect of Conantokin G on NMDA Receptor–Mediated Spontaneous EPSCs in Cultured Cortical Neurons

“…Conantokin G (Con G), a small 17 amino acid peptide isolated from fish-hunting snail, Conus geographus, is the best-characterized conantokin (Olivera 1997), which exerts its in vivo effects through the functional inhibition of NMDA receptors (Layer et al 2004). The potential of Con G as a neuroprotective agent in ischemic and excitotoxic brain injury, neuronal apoptosis, and Alzheimer's disease has been reported (Dave et al 2003;Ragnarsson et al 2002;Williams et al 2000).…”