Metabotropic glutamate receptors coupled to IP3 production mediate inhibition of IAHP in rat dentate granule neurons

Abstract

1. Whole cell recordings from dentate granule neurons in the hippocampal slice preparation reveal that (1 S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), a selective agonist at metabotropic glutamate receptors (mGluRs), inhibits a calcium-activated potassium current (IAHP) responsible for the postspike after-hyperpolarization. Inclusion of 1 mM of the Ca2+ chelator ethylene glycol-bis (beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid in the patch pipette reduced the inhibitory action of ACPD on IAHP 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 inhibitor action of ACPD. 2. Inhibition of IAHP is not secondary to effects on Ca2+ currents, because 10 microM ACPD, which inhibits IAHP by 95 +/- 5% (mean +/- SE), reduced the Ca2+ current by only 8 +/- 4%. 3. Activation of mGluRs accelerates the irreversible inhibition of IAHP that develops when 88 microM GTP-gamma-S is included in the pipette filling solution, whereas inclusion of 1 mM GDP-beta-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 mGluR1 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 microM) completely inhibited IAHP, and the mGluR1 antagonist (S)-4-carboxyphenylglycine (500 microM) reduced IAHP inhibition produced by 5 microM ACPD from 73 +/- 6% to 22 +/- 4%. These results indicate that the mGluR responsible for IAHP 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 microM ACPD to inhibit IAHP from almost 100% to 57 +/- 8% (n = 8). Heparin, an IP3 receptor antagonist that reduces Ca2+ mobilization, attenuated the inhibitory action 10 microM ACPD from almost 100% to 39 +/- 5% (n = 5). Heparin by itself increased the amplitude and duration of IAHP, suggesting that resting levels of IP3 are sufficient to suppress of IAHP partially. 6. In addition to the pool of intracellular Ca2+ that is mobilized by IP3, there is a distinct pool that is responsible for Ca(2+)-triggered Ca2+ release and is blocked by ryanodine or dantrolene. These drugs caused a small reduction of both IAHP 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 diacylglycerol and activation of protein kinase C (PKC). However, the inhibitory action of ACPD on IAHP was not aff...

Functional Specificity of Gαqand Gα11in the Cholinergic and Glutamatergic Modulation of Potassium Currents and Excitability in Hippocampal Neurons

“…The suppression of sI AHP by muscarinic agonists in CA1 neurons is instead linked to M 3 receptor activation (Rouse et al, 2000) and is mediated principally by G␣ q , in a similar way to that observed for the M 1 -mediated inhibition of the N-type calcium current in sympathetic neurons . The preponderant involvement of G␣ q in the M 3 -and mGluR 5 -mediated suppression of sI AHP presented in this study is in agreement with previous works using pharmacological approaches to show that G-proteins, and in particular pertussis toxin-insensitive ones, were essential components of the muscarinic and mGluR signal cascades converging on sI AHP (Dutar and Nicoll, 1988;Gerber et al, 1992;Abdul-Ghani et al, 1996a;Krause and Pedarzani, 2000). Beside modulating sI AHP , muscarinic and mGluR agonists induce a depolarization of the membrane potential in CA1 neurons.…”

“…The actions of both muscarinic and mGluR agonists on sI AHP have been shown to involve activation of G-proteins of the pertussis toxin-insensitive type (Dutar and Nicoll, 1988;Gerber et al, 1992;Abdul-Ghani et al, 1996a;Krause and Pedarzani, 2000). However, pertussis toxin and GDP-␤-S used in those studies blocked a wide subset or all G-proteins, respectively.…”

Increases in Intracellular Calcium Triggered by Channelrhodopsin-2 Potentiate the Response of Metabotropic Glutamate Receptor mGluR7

“…Thus, Ca 2ϩ release from intracellular stores might provide a molecular link between different mGluR subtypes because activation of group I mGluRs results in the production of inositol 1,4,5-trisphosphate, and hence, the release of stored Ca 2ϩ (36). Since both group I and III receptors have been shown to be presynaptic at the Schaffer collateral-CA1 synapse in the hippocampus (37), release of intracellular Ca 2ϩ could create another pathway for synergy between mGluRs, as postulated for some aspects of long term potentiation and long term depression (38).…”

Excitotoxicity: An Organized Crime at The Cellular Level

“…Variants from Group I are located in the postsynaptic membrane and potentiate excitotoxicity as key mediators of the later mechanisms. Through subunit Gq, PLC can be activated, initiating the triphosphate inositol pathway that results in calcium release from intracellular deposits, as observed in Figure 3 [36]. Conversely, group II and III are located in the presynaptic membrane, coupled with…”