Metabotropic glutamate receptors coupled to IP3 production mediate inhibition of I(AHP) in rat dentate granule neurons

Muhammed A. Abdul-Ghani, Taufik A. Valiante, Peter L. Carlen, Peter S. Pennefather

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87 Scopus citations


1. Whole cell recordings from dentate granule neurons in the hippocampal slice preparation reveal that (1S,3R)-1-aminocyclopentane-l,3-dicarboxylic acid (ACPD), a selective agonist at metabotropic glutamate receptors (mGluRs), inhibits a calcium-activated potassium current (I(AHP)) responsible for the postspike after hyperpolarization. Inclusion of 1 mM of the Ca2+ chelator ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid in the patch pipette reduced the inhibitory action of ACPD on I(AHP) while having no effect on a similar action of serotonin (5-HT). Thus the known action of ACPD of mobilizing intracellular Ca2+ may be involved in this inhibitory action of ACPD. 2. Inhibition of I(AHP) is not secondary to effects on Ca2+ currents, because 10 μM ACPD, which inhibits I(AHP) by 95 ± 5% (mean ± SE), reduced the Ca2+ current by only 8 ± 4%. 3. Activation of mGluRs accelerates the irreversible inhibition of I(AHP) that develops when 88 μM GTP-γ-S is included in the pipette filling solution, whereas inclusion of 1 mM GDP-β-S attenuated the inhibitory action of ACPD. These results indicate that the response to mGluR activation is G protein mediated. 4. Group I mGluRs, which includes mGluRl and mGluR5, are G-protein-coupled receptors that are known to stimulate phospholipase C (PLC)-mediated hydrolysis of phosphoinositides to produce 1,4,5-triphosphate (IP3), which in turn is known to mobilize the release of intracellular Ca2+ . The weak but selective mGluR1 agonist (S)-3-hydroxyphenylglycine (100 μM) completely inhibited I(AHP), and the mGluR1 antagonist (S)-4-carboxyphenylglycine (500 μM) reduced I(AHP) inhibition produced by 5 μM ACPD from 73 ± 6% to 22 ± 4%. These results indicate that the mGluR responsible for I(AHP) inhibition has a similar pharmacological profile to that of those coupled to IP3 production. 5. The effects of agents known to interfere with IP3 production and action also support IP3 involvement in ACPD action. Neomycin (1 mM in pipette solution), which should reduce IP3 production through inhibition of PLC, reduced the ability of 10 μM ACPD to inhibit I(AHP) from almost 100% to 57 ± 8% (n = 8). Heparin, an IP3 receptor antagonist that reduces Ca2+ mobilization, attenuated the inhibitory action of 10 μM ACPD from almost 100% to 39 ± 5% (n = 5). Heparin by itself increased the amplitude and duration of I(AHP), suggesting that resting levels of IP3 are sufficient to suppress of I(AHP) partially. 6. In addition to the pool of intracellular Ca2+ that is mobilized by IP3, there is a distinct pool that is responsible for Ca2+-triggered Ca2+ release and is blocked by ryanodine or dantrolene. These drugs caused a small reduction of both I(AHP) and the inhibitory action of ACPD. Possibly the Ca2+ signal mobilized by IP3 is partially amplified by Ca2+ released from the ryanodine-sensitive stores. 7. Activation of PLC can also lead to the production of diacyl glycerol and activation of protein kinase C (PKC). However, the inhibitory action of ACPD on I(AHP), was not affected by staurosporine at a concentration (1 μM) that inhibits both protein kinase A (PKA) and PKC and blocks the action of 5-HT to inhibit I(AHP). 8. Activation of PKA by the adenylate cyclase activator forskolin led to inhibition of I(AHP). Although activation of mGluR1 agonists can also stimulate adenylate cyclase and activate PKA, inhibition of PKA and the effect of forskolin on I(AHP) with the Walsh peptide did not affect ACPD inhibition of I(AHP). 9. All of our results support the hypothesis that mGluR-mediated inhibition of I(AHP) is initiated by the production of IP3 and the mobilization of intracellular Ca2+.

Original languageEnglish (US)
Pages (from-to)2691-2700
Number of pages10
JournalJournal of neurophysiology
Issue number4
StatePublished - Oct 1996
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Physiology


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