Metabotropic glutamate receptor subtypes independently modulate neuronal intracellular calcium

Abstract

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.

Hematopoietic Factor Erythropoietin Fosters Neuroprotection through Novel Signal Transduction Cascades

“…Interestingly, neuroprotection by EPO during excitotoxicity may require a transient increase in intracellular calcium concentration, because a decrease in intracellular calcium can negate any protection by EPO during glutamate administration (Morishita et al, 1997). Such observations concerning a potential synergistic function for neuronal protection by intracellular calcium are not unique and have been reported with other cellular receptor systems, such as those that involve G-protein-related pathways (Maiese et al, 1999). Neuronal injury during NO exposure also can be prevented by EPO, suggesting that the mechanism of EPO protection functions below the level of hypoxic and excitotoxic insults ).…”

Erythropoietin: Elucidating new cellular targets that broaden therapeutic strategies

“…In contrast to the early externalization of membrane PS residues, the cleavage of genomic DNA into fragments (Maiese et al, 1999;Maiese and Vincent, 2000a; is considered to be a later event during apoptotic injury (Dombroski et al, 2000;Jessel et al, 2002;Kang et al, 2003b;Maiese and Vincent, 2000b). Endonucleases lead to DNA degradation and have been differentiated based on their ionic sensitivities to zinc (Torriglia et al, 1997), magnesium (Sun and Cohen, 1994), and calcium (Maiese et al, 1999), an important regulator that can independently impair cell survival.…”

“…Endonucleases lead to DNA degradation and have been differentiated based on their ionic sensitivities to zinc (Torriglia et al, 1997), magnesium (Sun and Cohen, 1994), and calcium (Maiese et al, 1999), an important regulator that can independently impair cell survival. In the nervous system, three separate endonuclease activities are present.…”

Erythropoietin and Oxidative Stress

“…In contrast to the early externalization of membrane PS residues, the cleavage of genomic DNA into fragments (Maiese, et al, 1999, Maiese and Vincent, 2000a, Maiese and Vincent, 2000b) is considered to be a later event during apoptotic injury (Dombroski, et al, 2000, Jessel, et al, 2002, Maiese and Vincent, 2000b. Endonucleases lead to DNA degradation and have been differentiated based on their ionic sensitivities to zinc (Torriglia, et al, 1997), magnesium (Sun and Cohen, 1994), and calcium (Maiese, et al, 1999), an important regulator that can independently impair cell survival.…”