Permissive Effect of Voltage on mGlu 7 Receptor Subtype Signaling in Neurons

Abstract

G protein-coupled receptors mobilize neuronal signaling cascades which until now have not been shown to depend on the state of membrane depolarization. Thus we have previously shown that the metabotropic glutamate receptor type 7 (mGlu7 receptor) blocks P/Q-type Ca 2؉ channels via activation of a G o protein and PKC, in cerebellar granule cells. We show here that the transient depolarizations used to evoke the studied Ca 2؉ current were indeed permissive to activate this pathway by a mGlu7 receptor agonist. Indeed, sustained depolarization to 0 mV was sufficient to inhibit P/Q-type Ca 2؉ channels. This effect involved a conformational change in voltage-gated sodium channel independently of Na ؉ flux, activation of a pertussis toxin-sensitive G-protein, inositol trisphosphate formation, intracellular Ca 2؉ release, and PKC activity. Subliminal sustained membrane depolarization became efficient in inducing inositol trisphosphate formation, release of intracellular Ca 2؉ and in blocking Ca 2؉ channels, when applied concomitantly with the mGlu7a receptor agonist, D,L-aminophosphonobutyrate. This synergistic effect of membrane depolarization and mGlu7 receptor activation provides a mechanism by which neuronal excitation could control action of the mGlu7 receptor in neurons.The excitatory neurotransmitter, glutamate, mediates its effects by activating ionotropic and metabotropic (mGlu) receptors. Eight genes encoding mGlu receptors have been identified and classified into three groups. The group I (mGlu1 and mGlu5 receptors) activates PLC through a G q protein, whereas group II (mGlu2 and mGlu3 receptors) and group III (mGlu4, mGlu6, mGlu7, and mGlu8 receptors) are coupled to G i /G o proteins (1). These receptors are widely distributed throughout the mammalian brain (2-5), but only the mGlu7 receptor subtype is almost exclusively localized at presynaptic sites (6 -8).Group II and III mGlu receptors, and particularly the mGlu7 receptor subtype, inhibit synaptic transmission (1, 9). Thus in vitro studies have shown that stimulation of mGlu7 receptors decreases release of glutamate in cerebellar cultures (10) and GABA in striatal cultures (11), promoting neuroprotection and excitotoxicity, respectively. Moreover, we have recently shown that mGlu7 receptors selectively block P/Q-type Ca 2ϩ channels in neurons (12), and these channels control transmitter release (13). Together these studies suggest that mGlu7 receptors play an important role in the modulation of synaptic transmission.Recent studies have pointed out that in the rat locus coeruleus, group III mGlu receptor agonists down-regulate high but not low frequency synaptic activity (14), suggesting that this receptor action depends on the state of neuronal depolarization. Moreover, a voltage-dependent activation of a G o protein has recently been shown in rat brain synaptoneurosomes (15). In light of these results, and because the mGlu7 receptor is coupled to a G o protein, this receptor is a potential candidate for mobilization of both voltage-and G o protein-depen...

Neural substrates for the distinct effects of presynaptic group III metabotropic glutamate receptors on extinction of contextual fear conditioning in mice

“…The facilitation of extinction acquisition mediated by AMN082, besides being possibly due to an activity-dependent depression of neurotransmission (Perroy et al., 2002; Ugolini et al., 2008), could also be ascribed to a functional blockade of mGlu7 receptors. In fact, it has been shown that AMN082 in addition to stimulating can induce the internalization of mGlu7 receptors (Pelkey et al., 2007).…”

Group III metabotropic glutamate receptors as autoreceptors in the cerebellar cortex

“…A number of studies have shown that depolarization per se during agonist exposure can be of relevance for GPCR signalling. Depolarization may weaken the signalling (Brody & Yue, 2000; Ilouz et al ., 1999; Stefani et al ., 1998) or strengthen it (Perroy et al ., 2002). Modulation of pharmacological properties due to receptor localization which might involve interaction with different protein binding partners has also been described (Davare et al ., 2001; Tabata et al ., 2002).…”

Target‐cell‐dependent plasticity within the mossy fibre–CA3 circuit reveals compartmentalized regulation of presynaptic function at divergent release sites

“…Indeed, mGluR7 directly interacts with the PKC scaffolding protein PICK1, and this interaction along with PKC activity is necessary for mGluR7‐mediated depression of release from cerebellar granule cells (Boudin et al 2000; Dev et al 2000; El Far et al 2000; Perroy et al 2002 a ; Enz & Croci, 2003). Most interestingly, PKC acting downstream of mGluR7 activation has been reported to persistently depress P/Q‐type voltage‐gated calcium channels (VGCCs; Perroy et al 2000, 2002 b ). Similarly, using combined electrophysiological recording and two‐photon Ca 2+ imaging techniques, we recently found that presynaptic MF–SLIN LTD is ultimately expressed as a persistent reduction in P/Q‐type VGCC function (Fig.…”