Regulation of phosphoinositide turnover in neonatal rat cerebral cortex by group I‐ and II‐ selective metabotropic glutamate receptor agonists

Regulation of phosphoinositide turnover in neonatal rat cerebral cortex by group I‐ and II‐... The interactive effects of different metabotropic glutamate (mGlu) receptor subtypes to regulate phosphoinositide turnover have been studied in neonatal rat cerebral cortex and hippocampus by use of agonists and antagonists selective between group I and II mGlu receptors. The group II‐selective agonist 2R,4R‐4‐aminopyrrolidine‐2,4‐dicarboxylate (2R,4R‐APDC; 100 μM) had no effect on basal total inositol phosphate ((3H)‐InsPx) accumulation (in the presence of Li+) in myo‐(3H)‐inositol pre‐labelled slices, but enhanced the maximal (3H)‐InsPx response to the group I‐selective agonist (S)‐3,5‐dihydroxyphenylglycine (DHPG) by about 100% in both hippocampus and cerebral cortex. In cerebral cortex the enhancing effect of 2R,4R‐APDC occurred with respect to the maximal responsiveness and had no effect on EC50 values for DHPG (‐log EC50 (M): control, 5.56±0.05; +2R,4R‐APDC, 5.51±0.08). 2R,4R‐APDC also caused a significant enhancement of the DHPG‐stimulated inositol 1,4,5‐trisphosphate (Ins(1,4,5)P3) mass response over an initial 0–300 s time‐course. The enhancing effects of 2R,4R‐APDC on DHPG‐stimulated (3H)‐InsPx accumulation were observed in both the presence and nominal absence of extracellular Ca2+, and irrespective of whether 2R,4R‐APDC was added before, simultaneous with, or subsequent to DHPG. Furthermore, increasing the tissue cyclic AMP concentration up to 100 fold had no effect on DHPG‐stimulated Ins(1,4,5)P3 accumulation in the absence or presence of 2R,4R‐APDC. 2R,4R‐APDC and (2S, 1′R, 2′R, 3′R)‐2‐(2,3‐dicarboxylcyclopropyl)glycine (DCG‐IV), the latter agent in the presence of MK‐801 to prevent activation of NMDA‐receptors, each inhibited forskolin‐stimulated cyclic AMP accumulation by about 50%, with respective EC50 values of 1.3 and 0.04 μM (‐log EC 50 (M): 2R,4R‐APDC, 5.87±0.09; DCG‐IV, 7.38±0.05). In the presence of DHPG (30 μM), 2R,4R‐APDC and DCG‐IV also concentration‐dependently increased (3H)‐InsPx accumulation with respective EC50 values of 4.7 and 0.28 μM (‐log EC50 (M): 2R,4R‐APDC, 5.33±0.04; DCG‐IV, 6.55±0.09) which were 3–7 fold rightward‐shifted relative to the adenylyl cyclase inhibitory responses. The group II‐selective mGlu receptor antagonist LY307452 (30 μM) caused parallel rightward shifts in the concentration‐effect curves for inhibition of forskolin‐stimulated adenylyl cyclase, and enhancement of DHPG‐stimulated (3H)‐InsPx accumulation, by 2R,4R‐APDC yielding similar equilibrium dissociation constants (Kds, 3.7±1.1 and 4.1±0.4 μM respectively) for each response. The ability of 2R,4R‐APDC to enhance receptor‐mediated (3H)‐InsPx accumulation appeared to be agonist‐specific; thus although DHPG (100 μM) and the muscarinic cholinoceptor agonist carbachol (10 μM) stimulated similar (3H)‐InsPx accumulations, only the response to the former agonist was enhanced by co‐activation of group II mGlu receptors. These data demonstrate that second messenger‐generating phosphoinositide responses stimulated by group I mGlu receptors are positively modulated by co‐activation of group II mGlu receptors in cerebral cortex and hippocampus. The data presented here are discussed with respect to the possible mechanisms which might mediate the modulatory activity, and the physiological and pathophysiological significance of such crosstalk between mGlu receptors. British Journal of Pharmacology (1998) 123, 581–589; doi:10.1038/sj.bjp.0701626 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

Regulation of phosphoinositide turnover in neonatal rat cerebral cortex by group I‐ and II‐ selective metabotropic glutamate receptor agonists

Loading next page...
 
/lp/wiley/regulation-of-phosphoinositide-turnover-in-neonatal-rat-cerebral-AQu0DlyRmm
Publisher
Wiley
Copyright
1998 British Pharmacological Society
ISSN
0007-1188
eISSN
1476-5381
DOI
10.1038/sj.bjp.0701626
pmid
9504400
Publisher site
See Article on Publisher Site

Abstract

The interactive effects of different metabotropic glutamate (mGlu) receptor subtypes to regulate phosphoinositide turnover have been studied in neonatal rat cerebral cortex and hippocampus by use of agonists and antagonists selective between group I and II mGlu receptors. The group II‐selective agonist 2R,4R‐4‐aminopyrrolidine‐2,4‐dicarboxylate (2R,4R‐APDC; 100 μM) had no effect on basal total inositol phosphate ((3H)‐InsPx) accumulation (in the presence of Li+) in myo‐(3H)‐inositol pre‐labelled slices, but enhanced the maximal (3H)‐InsPx response to the group I‐selective agonist (S)‐3,5‐dihydroxyphenylglycine (DHPG) by about 100% in both hippocampus and cerebral cortex. In cerebral cortex the enhancing effect of 2R,4R‐APDC occurred with respect to the maximal responsiveness and had no effect on EC50 values for DHPG (‐log EC50 (M): control, 5.56±0.05; +2R,4R‐APDC, 5.51±0.08). 2R,4R‐APDC also caused a significant enhancement of the DHPG‐stimulated inositol 1,4,5‐trisphosphate (Ins(1,4,5)P3) mass response over an initial 0–300 s time‐course. The enhancing effects of 2R,4R‐APDC on DHPG‐stimulated (3H)‐InsPx accumulation were observed in both the presence and nominal absence of extracellular Ca2+, and irrespective of whether 2R,4R‐APDC was added before, simultaneous with, or subsequent to DHPG. Furthermore, increasing the tissue cyclic AMP concentration up to 100 fold had no effect on DHPG‐stimulated Ins(1,4,5)P3 accumulation in the absence or presence of 2R,4R‐APDC. 2R,4R‐APDC and (2S, 1′R, 2′R, 3′R)‐2‐(2,3‐dicarboxylcyclopropyl)glycine (DCG‐IV), the latter agent in the presence of MK‐801 to prevent activation of NMDA‐receptors, each inhibited forskolin‐stimulated cyclic AMP accumulation by about 50%, with respective EC50 values of 1.3 and 0.04 μM (‐log EC 50 (M): 2R,4R‐APDC, 5.87±0.09; DCG‐IV, 7.38±0.05). In the presence of DHPG (30 μM), 2R,4R‐APDC and DCG‐IV also concentration‐dependently increased (3H)‐InsPx accumulation with respective EC50 values of 4.7 and 0.28 μM (‐log EC50 (M): 2R,4R‐APDC, 5.33±0.04; DCG‐IV, 6.55±0.09) which were 3–7 fold rightward‐shifted relative to the adenylyl cyclase inhibitory responses. The group II‐selective mGlu receptor antagonist LY307452 (30 μM) caused parallel rightward shifts in the concentration‐effect curves for inhibition of forskolin‐stimulated adenylyl cyclase, and enhancement of DHPG‐stimulated (3H)‐InsPx accumulation, by 2R,4R‐APDC yielding similar equilibrium dissociation constants (Kds, 3.7±1.1 and 4.1±0.4 μM respectively) for each response. The ability of 2R,4R‐APDC to enhance receptor‐mediated (3H)‐InsPx accumulation appeared to be agonist‐specific; thus although DHPG (100 μM) and the muscarinic cholinoceptor agonist carbachol (10 μM) stimulated similar (3H)‐InsPx accumulations, only the response to the former agonist was enhanced by co‐activation of group II mGlu receptors. These data demonstrate that second messenger‐generating phosphoinositide responses stimulated by group I mGlu receptors are positively modulated by co‐activation of group II mGlu receptors in cerebral cortex and hippocampus. The data presented here are discussed with respect to the possible mechanisms which might mediate the modulatory activity, and the physiological and pathophysiological significance of such crosstalk between mGlu receptors. British Journal of Pharmacology (1998) 123, 581–589; doi:10.1038/sj.bjp.0701626

Journal

British Journal of PharmacologyWiley

Published: Feb 1, 1998

References

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create folders to
organize your research

Export folders, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month