Metabotropic glutamate receptor subtypes independently modulate neuronal intracellular calcium.
Metabotropic glutamate receptors (mGluRs) modulate several G-protein-related signal transduction pathways including intracellular calcium (iCa(2+)) that control both neuronal development and demise. As an initial investigation, we characterized the ability of specific mGluR subtypes to modulate iCa(2+) by using Fura-2 microfluorometry in primary hippocampal neurons. Activation rather than inhibition of the metabotropic system with the group I and group II mGluR agonist 1S, 3R-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), the specific group I agonist (S)-3,5-dihydroxyphenylglycine (DHPG), and the specific group II agonist (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (LCCG-I) increased iCa(2+) with increasing concentrations. In contrast, the group III mGluR agonist, L(+)-2-amino-4-phosphonobutyric acid (L-AP4) produced no significant increase in iCa(2+). Through the pharmacological modulation of individual mGluR subtypes, we further examined the role of iCa(2+) release by the mGluR system. Release of iCa(2+) by both 1S,3R-ACPD and LCCG-I was prevented only through the administration of the antagonists (2S)-alpha-ethylglutamic acid (EGlu; mGluR2 and mGluR3) and (2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-phenylcyclopropyl)glycine (PCCG-IV; mGluR2), suggesting that the mGluR2 subtype was responsible for the release of iCa(2+). As a control, the group I antagonists, L(+)-2-amino-3-phosphonopropionic acid (L-AP3) and (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA), prevented DHPG release of iCa(2+) but were ineffective against iCa(2+) release by 1S,3R-ACPD. Although extracellular calcium influx did not significantly contribute to the release of iCa(2+) by the mGluR system, pharmacological inhibition of calcium-induced calcium-release-sensitive calcium pools played a critical role in the release of iCa(2+). Further characterization of the cellular calcium pools modulated by the mGluR subtypes may provide greater insight into the mechanisms that mediate neuronal function.
Maiese
K
K
Laboratory of Cellular and Molecular Cerebral Ischemia, Wayne State University School of Medicine, Detroit, Michigan 48201, USA. kmaiese@med.wayne.edu
Ahmad
I
I
TenBroeke
M
M
Gallant
J
J
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003521:Cyclopropanes / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism; D007189:Indans / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000145:classification / Q000187:drug effects / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology
C095756:1-aminoindan-1,5-dicarboxylic acid; C099854:2-(2'-carboxy-3'-phenylcyclopropyl)glycine; D003521:Cyclopropanes; D018691:Excitatory Amino Acid Antagonists; D007189:Indans; D017470:Receptors, Glutamate; D018094:Receptors, Metabotropic Glutamate; C000211:2-amino-3-phosphonopropionic acid; D000409:Alanine; D002118:Calcium; D005998:Glycine