Disease relevance of Grm4

• In the ganglion cell layer, virtually every ganglion cell and displaced amacrine cell was labelled for mGluR1 and mGluR4 [1].
• Changes in metabotropic glutamate receptor mRNA levels following global ischemia: increase of a putative presynaptic subtype (mGluR4) in highly vulnerable rat brain areas [2].
• We conclude that activation of the mGluR4 receptor protects hippocampal neurons from NO toxicity and that the mechanism of NO induced neurodegeneration does not appear to involve inhibition of the mGluR1 receptor subtype activity or the phosphoinositide system [3].
• Group II (mGluR2 and 3) and group III mGluR (mGluR4, 6, 7, 8) are novel targets for inhibition of vagal signaling with therapeutic potential in, for example, GERD [4].
• When medium-sized spiny neurons (MSNs) were labeled with Sindbis virus expressing membrane-targeted green fluorescent protein, mGluR4 immunoreactivity was observed on some varicosities of their axon collaterals in immunofluorescence and immunoelectron microscopies [5].

High impact information on Grm4

• We previously identified the metabotropic glutamate receptor 4 (mGluR4) as a potential drug target and predicted that selective activation of mGluR4 could provide palliative benefit in PD [6].
• This compound selectively potentiated agonist-induced mGluR4 activity in cultured cells expressing this receptor and did not itself act as an agonist [6].
• The closely related analogue 7-(hydroxylimino)cyclopropachromen-1a-carboxamide ethyl ester, which does not potentiate mGluR4, had no effect in this model [6].
• Upregulation of presynaptic mGluR4 in pup CA3 neurons could lead to reduced transmitter release from CA3 axons, including recurrent collaterals, thereby reducing vulnerability of neonatal CA3 neurons to seizure-induced damage [7].
• These data are consistent with a largely presynaptic role of mGluR7 in the hippocampus and suggest that mGluR4 may have both presynaptic and postsynaptic functions [8].

Biological context of Grm4

• We studied the signal transduction mechanism and pharmacological characteristics of the rat mGluR3 and mGluR4 subtypes in Chinese hamster ovary cells permanently expressing the cloned receptors [9].
• On the other hand, a selective mGluR4 antagonist, (RS)-alpha-cyclopropyl-4-phosphono-phenylglycine, induces apoptosis even in the presence of elevated K+ [10].
• Downregulation of mGluR-4 messenger RNA (mRNA) does not occur if low K+-induced death is prevented by treatment with insulin-like growth factor I or adenosine 3',5'-cyclic monophosphate [10].
• 1. In the rodent cerebellum, both presynaptic CB1 cannabinoid receptors and presynaptic mGluR4 metabotropic glutamate receptors acutely depress excitatory synaptic transmission at parallel fibre-Purkinje cell synapses [11].

Anatomical context of Grm4

• The mGluR4 mRNA was abundant in most thalamic nuclei, with prominent expression in the CM/CL, Po and ventrobasal complex (VPM and ventroposterolateral, VPL) [12].
• The expression pattern of mGluR4 mRNA is more restricted, and this expression is prominent in the cerebellum, olfactory bulb, and thalamus [9].
• The mGluR4 mRNA was also increased in the parietal cortex, whereas the ventral posteromedial thalamic nucleus showed a small decrease in its mRNA content [2].
• One source of mGluR4 staining in the superior colliculus may thus be retinal axons, although other sources cannot be entirely excluded [13].
• Staining for the Group III receptor, mGluR4, was dense in the superficial superior colliculus in all species, with characteristics suggesting nerve fibre staining. mGluR4 staining was seen in the cat optic nerve/optic tract [13].

Associations of Grm4 with chemical compounds

• These data are consistent with the possibility that in primary cultures of cerebellar neurons, phosphoinositide responses may be predominantly mediated by mGluR1a, rather than mGluR5, and that cAMP inhibition involves preferentially mGluR4 and mGluR3 [14].
• Three groups of mGluRs have been described: group 1 (mGluR1 and 5) receptors are positively coupled to phospholipase C whereas group 2 (mGluR2 and 3) and group 3 (mGluR4, 6, 7 and 8) receptors are negatively coupled to adenylate cyclase [15].
• Activation of group I receptors (mGluR1 and/or mGluR5) on presynaptic somata/dendrites led to an increase in spike-dependent transmitter release, whereas activation of the group III receptors (mGluR4, 7, and/or 8) on presynaptic terminals suppressed glutamate and GABA release onto SON neurons [16].
• [(3)H]L-AP4 binding to mGluR4 required chloride ions but not monovalent or divalent cations [17].
• In parallel experiments, no activities of these phenylglycine analogs at mGluR4 were observed [18].

Other interactions of Grm4

• Consistent with previous studies, one receptor subtype is an L-AP4-sensitive receptor that is pharmacologically similar to mGluR4 or mGluR7 [19].
• Intrathecal (i.t.) administration of the mGluR4/mGluR6-mGluR8 agonist, L(+)-2-amino-4-phosphonobutyric acid (L-AP4), the mGluR1/mGluR5 antagonists [20].
• Both mGluR3 and mGluR4 inhibit the forskolin-stimulated accumulation of intracellular cAMP formation in response to agonist interaction [9].
• Maintaining the granule neurons in vitro in 10 mM KCl increased the absolute amount of mRNAs encoding mGluR2 and mGluR4 at 9 and 13 days in vitro [14].
• RT-PCR and immunological analyses indicated that mGluR4, a class III mGluR, was expressed and localized with alpha- and F cells, whereas no evidence for expression of other mGluRs, including mGluR8, was obtained [21].

Analytical, diagnostic and therapeutic context of Grm4

• After 24 hours of reperfusion the mRNA levels were significantly increased for mGluR2 and mGluR4 while it was significantly decreased for mGluR5 [22].
• Immunoblotting showed moderate levels of mGluR2/3 and mGluR4 and strong levels of mGluRS [23].
• In this preparation, two mGluRs with high and low affinity for l(+)-2-amino-4-phosphonobutyrate were identified by immunocytochemistry as mGluR4 and mGluR7, respectively [24].
• The distribution of mRNAs for metabotropic glutamate receptors, mGluR4 and mGluR7, which are highly sensitive for L-2-amino-4-phosphonobutyrate (L-AP4), was examined in the central nervous system of the rat by in situ hybridization [25].
• Northern blot analyses demonstrated the presence of olfactory rosette RNA that hybridizes with cDNA probes for mGluR1 and mGluR4 under low stringency conditions [26].

References