Related Experiment Videos
Divalent cations modulate N-methyl-D-aspartate receptor function at the glycine site
H Hashemzadeh-Gargari1, T R Guilarte
1Department of Environmental Health Sciences, The Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland, USA.
The Journal of Pharmacology and Experimental Therapeutics
|August 24, 1999
Summary
Divalent cations like calcium and magnesium modulate N-methyl-D-aspartate receptor (NMDAR) function by affecting the glycine binding site. This modulation changes during development and can be blocked by heavy metals like lead and zinc.
Area of Science:
- Neuroscience
- Neuropharmacology
- Biochemistry
Background:
- The N-methyl-D-aspartate receptor (NMDAR) is a crucial ionotropic glutamate receptor involved in synaptic plasticity and neurotransmission.
- Divalent cations are known to influence NMDAR function, but their specific modulatory mechanisms, especially concerning the glycine binding site, require further elucidation.
Purpose of the Study:
- To investigate the modulatory effects of divalent cations, specifically calcium (Ca2+) and magnesium (Mg2+), on NMDAR function.
- To examine the developmental changes in divalent cation modulation of NMDARs.
- To determine the interaction of heavy metals, lead (Pb2+) and zinc (Zn2+), with divalent cation-mediated NMDAR potentiation.
Main Methods:
- Utilized radioligand binding assays with [(3)H]MK-801 to assess NMDAR function in adult rat brain membranes.
- Investigated the effects of varying concentrations of Ca2+ and Mg2+ on [(3)H]MK-801 binding.
- Examined the ontogeny of divalent cation potentiation by analyzing NMDAR binding sites at different postnatal ages.
- Assessed the impact of Pb2+ and Zn2+ on Ca2+- and Mg2+-induced NMDAR potentiation.
Main Results:
- Ca2+ and Mg2+ exhibited a biphasic effect on [(3)H]MK-801 binding, potentiating it at micromolar concentrations and inhibiting at higher concentrations.
- Potentiation by Ca2+ and Mg2+ was attributed to an increase in the maximal number of binding sites (Bmax), not altered binding affinity (Kd), suggesting an effect on the glycine site.
- Divalent cation-mediated potentiation of NMDAR binding sites increased from low levels shortly after birth to a peak at 17 days, then declined to adult levels.
- The potency of Ca2+ and Mg2+ in stimulating binding remained constant across ages.
- Pb2+ and Zn2+ antagonized the potentiating effects of Ca2+ and Mg2+ on NMDARs.
Conclusions:
- Divalent cations differentially regulate NMDAR function, primarily through modulation of the glycine binding site.
- The NMDAR glycine site plays a significant role in regulating glutamatergic neurotransmission influenced by physiologically and toxicologically relevant cations.
- Developmental changes in divalent cation modulation highlight the dynamic nature of NMDAR regulation throughout maturation.