Biomaterial Database

Metabotropic glutamate receptors prevent programmed cell death through the modulation of neuronal endonuclease activity and intracellular pH. 1999

A M Vincent, and M TenBroeke, and K Maiese

Departments of Neurology and Anatomy and Cell Biology, Center for Molecular Medicine and Genetics, Detroit, Michigan, 48201, USA.

Metabotropic glutamate receptor (mGluR) activation prevents neurodegeneration against nitric oxide (NO)-induced programmed cell death (PCD). We therefore investigated whether specific neuronal endogenous deoxyribonucleases, enzymes recently identified to be responsible for the maintenance of DNA integrity, mediated mGluR protection against NO. In rat primary hippocampal neurons, injury was assessed by using a 0.4% trypan blue dye exclusion method and TUNEL assay 24 h following treatment with the NO generators sodium nitroprusside (300 microM) or SIN-1 (300 microM). DNA digestion studies using neuronal cell extracts were employed to assess specific endonuclease activity. Individual application of aurintricarboxylic acid (ATA) (10 microM), an endonuclease inhibitor, or the mGluR agonists 1S,3R-ACPD (750 microM), DHPG (750 microM), L-CCG-I (750 microM), or L-AP4 (750 microM) prior to NO exposure significantly increased neuronal survival. Yet, combination therapy with ATA (10 microM) and the mGluR agonists did not synergistically improve neuronal survival, suggesting a common pathway of protection for ATA and the mGluRs that is dependent upon the modulation of neuronal endonuclease activity. In further support of this premise, protection by the mGluR agonists 1S,3R-ACPD, DHPG, L-CCG-I, and L-AP4 was significantly decreased during enhancement of endonuclease activity with the zinc chelator, N,N,N',N',-tetrakis (2-pyridylmethyl) ethylenediamine. Antagonism of the mGluR system was ineffective against endonuclease induced DNA destruction. Further assessment with DNA digestion assays identified two distinct mechanisms to maintain DNA integrity, a Ca2+/Mg2+-dependent endonuclease inhibited by L-AP4 and a magnesium dependent endonuclease inhibited by 1S,3R-ACPD. These neuroprotective mechanisms during activation of the mGluR system were also intricately linked to the active reversal of the biphasic intracellular pH changes induced by NO. Further investigation into the molecular pathways modulated by mGluRs may identify specific mechanisms that can maintain DNA integrity during adverse cellular environments.

UI	MeSH Term	Description	Entries
D007425	Intracellular Membranes	Thin structures that encapsulate subcellular structures or ORGANELLES in EUKARYOTIC CELLS. They include a variety of membranes associated with the CELL NUCLEUS; the MITOCHONDRIA; the GOLGI APPARATUS; the ENDOPLASMIC RETICULUM; LYSOSOMES; PLASTIDS; and VACUOLES.	Membranes, Intracellular,Intracellular Membrane,Membrane, Intracellular
D008274	Magnesium	A metallic element that has the atomic symbol Mg, atomic number 12, and atomic weight 24.31. It is important for the activity of many enzymes, especially those involved in OXIDATIVE PHOSPHORYLATION.
D009474	Neurons	The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM.	Nerve Cells,Cell, Nerve,Cells, Nerve,Nerve Cell,Neuron
D002118	Calcium	A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes.	Coagulation Factor IV,Factor IV,Blood Coagulation Factor IV,Calcium-40,Calcium 40,Factor IV, Coagulation
D002478	Cells, Cultured	Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.	Cultured Cells,Cell, Cultured,Cultured Cell
D004720	Endonucleases	Enzymes that catalyze the hydrolysis of the internal bonds and thereby the formation of polynucleotides or oligonucleotides from ribo- or deoxyribonucleotide chains. EC 3.1.-.	Endonuclease
D006624	Hippocampus	A curved elevation of GRAY MATTER extending the entire length of the floor of the TEMPORAL HORN of the LATERAL VENTRICLE (see also TEMPORAL LOBE). The hippocampus proper, subiculum, and DENTATE GYRUS constitute the hippocampal formation. Sometimes authors include the ENTORHINAL CORTEX in the hippocampal formation.	Ammon Horn,Cornu Ammonis,Hippocampal Formation,Subiculum,Ammon's Horn,Hippocampus Proper,Ammons Horn,Formation, Hippocampal,Formations, Hippocampal,Hippocampal Formations,Hippocampus Propers,Horn, Ammon,Horn, Ammon's,Proper, Hippocampus,Propers, Hippocampus,Subiculums
D006859	Hydrogen	The first chemical element in the periodic table with atomic symbol H, and atomic number 1. Protium (atomic weight 1) is by far the most common hydrogen isotope. Hydrogen also exists as the stable isotope DEUTERIUM (atomic weight 2) and the radioactive isotope TRITIUM (atomic weight 3). Hydrogen forms into a diatomic molecule at room temperature and appears as a highly flammable colorless and odorless gas.	Protium,Hydrogen-1
D006863	Hydrogen-Ion Concentration	The normality of a solution with respect to HYDROGEN ions; H+. It is related to acidity measurements in most cases by pH	pH,Concentration, Hydrogen-Ion,Concentrations, Hydrogen-Ion,Hydrogen Ion Concentration,Hydrogen-Ion Concentrations
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia