Disease relevance of Dihydroxyphenylglycine

• We have found that dihydroxyphenylglycine-activated protein synthesis in synaptoneurosomes is dramatically reduced in a knockout mouse model of fragile X syndrome, which cannot produce full-length FMRP, suggesting that FMRP is involved in or required for this process [1].
• Intracellular messengers involved in spontaneous pain, heat hyperalgesia, and mechanical allodynia induced by intrathecal dihydroxyphenylglycine [2].
• Treatment of cultures with the antisense (24 h) but not scrambled sequence oligonucleotide suppressed DHPG-induced increase in Rab5b expression and significantly disrupted DHPG-induced protection against NMDA toxicity in a concentration-dependent manner (0.01-10 nM) [3].

High impact information on Dihydroxyphenylglycine

• Here, we show that transient activation of group I mGluR with the selective agonist (S)-3,5-dihydroxyphenylglycine (DHPG) activates p38 MAPK through G protein betagamma-subunit, small GTPase Rap1, and MAPK kinase 3/6 (MKK3/6), thus resulting in mGluR5-dependent LTD [4].
• Thus, the nocifensive response to intrathecal injection of the group I mGluR agonist (RS)-3,5-Dihydroxyphenylglycine (DHPG) is significantly potentiated seven days following Complete Freund's Adjuvant (CFA)-induced inflammation of the hind paw [5].
• DHPG-induced ERK phosphorylation in the dorsal horn is not potentiated following inflammation [5].
• However, inhibiting ERK activation using a MEK inhibitor, U0126, following inflammation attenuates the intrathecal DHPG-induced behavioral responses to a greater extent than in control animals [5].
• Intrastriatal infusion of the group I agonist 3,5-dihydroxyphenylglycine (DHPG) at 100 and 250 nM also increased CREB and Elk-1 phosphorylation [6].

Biological context of Dihydroxyphenylglycine

• Pre-treatment of okadaic acid (0.05 nm) did not alter DHPG-induced increases in the phosphorylation of the two transcription factors [6].
• This suggests that presynaptic changes in transmitter release contribute to the depression of synaptic transmission by DHPG [7].
• Intracellular recording was used to examine the correspondence between excitatory postsynaptic potentials (EPSPs) and action potentials with components of the field potential, and to further investigate the action of DHPG [8].
• Consistent with this, DHPG-induced depotentiation did not restore the ability of high-frequency stimulation to induce LTP at synapses that had previously undergone saturating levels of LTP [9].
• At resting membrane potential, no significant change in the current was induced by DHPG, although a decrease in membrane conductance was seen [10].

Anatomical context of Dihydroxyphenylglycine

• The mechanisms responsible for the induction and expression of DHPG-induced LTD in the CA1 region of the hippocampus are currently the subject of intense investigation [11].
• Activation of mGluRs with DHPG, but not ACPD, induced LTD at both Schaffer collateral/commissural fiber synapses onto CA1 pyramidal cells and at associational/commissural fiber synapses onto CA3 pyramidal cells [7].
• The selective group I mGluR agonist, (RS)-3,5-dihydroxyphenylglycine (DHPG), evoked a transient increase in intracellular Ca2+ levels ([Ca2+]i), within neuronal somas and apical dendrites, together with a relatively long lasting inward current (I(DHPG)) [12].
• Effect of the group I metabotropic glutamate agonist DHPG on the visual cortex [13].
• METHODS: Pilocarpine (10 microM) in 7.5 mM[K+]o or DHPG (100 microM) in 5 mM[K+]o artificial cerebrospinal fluid (ACSF) were bath applied to hippocampal slices, and extracellular recordings were made from the CA3 region [14].

Associations of Dihydroxyphenylglycine with other chemical compounds

• Enhancing Ca(2+) influx by prolonging action potential duration with bath applications of the K(+) channel blocker 4-aminopyridine (4-AP) also strongly reduced the effects of DHPG in the presence of normal [Ca(2+)](o) (2 mM) [7].
• The mGluR agonists (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) and (R,S)-3,5-dihydroxyphenylglycine (DHPG) induced [Ca2+]i responses in 76 and 93% of the cells, respectively [15].
• In addition, DHPG-induced stimulation of the cotransporter activity was inhibited in the presence of mGluRs antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA) (1 mM) and also with selective mGluR1 antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) (100 microM) [16].
• Administration of the Group 1 metabotropic glutamate receptor (mGluR) agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) facilitates ("primes") subsequent long-term potentiation (LTP) through a phospholipase C signaling cascade that may involve release of Ca(2+) from the endoplasmic reticulum (ER) [17].
• CONCLUSIONS: Ictal discharges produced by pilocarpine or DHPG depended on intact synaptic transmission mediated by AMPA/KA receptors, release of calcium from intracellular stores, and L-type calcium channel activation [14].

Gene context of Dihydroxyphenylglycine

• In a dorsal horn slice preparation, the group I (dihydroxyphenylglycine), but not group II [(2R,4R)-4-aminopyrrolidine-2,3-dicarboxylate] and III [L-AP 4 (L-(+)-2-amino-4-phosphonobutyric acid)], mGluR agonists, an IP3 receptor (D-IP3) agonist, and a PKC (PMA) activator, induces NR2B tyr-P similar to that seen in vivo after inflammation [18].
• Taken together, these results argue that in CA1 pyramidal cells in the adult rat, DHPG activates mGluRs of both the mGluR5 and mGluR1 subtypes, causing a long-lasting suppression of the sAHP and a consequent persistent increase in excitability via a PLC-, PKC-, and IP(3)-independent transduction pathway [19].
• Here we show that simultaneous pharmacological blockade of mGluR1 and mGluR5 is required to block induction of LTD by the group 1 mGluR agonist, (RS)-3,5-dihydroxyphenylglycine (DHPG) [20].
• The DHPG-induced expression of immediate early genes (c-fos, junB, egr1 and nr4a1) was subsequently verified by TaqMan polymerase chain reaction [21].
• The phosphorylation of the ternary complex factor Elk-1 and its localization in the nucleus of hippocampal neurones after DHPG treatment was shown by immunofluorescence using a phosphospecific antibody [21].

Analytical, diagnostic and therapeutic context of Dihydroxyphenylglycine

• Western immunoblotting of samples prepared from DHPG-treated slices revealed, however, that activation of group I mGluRs causes a transient increase in phosphorylation of AMPA receptor GluR1 subunits at sites crucial for LTP and under some conditions causes persistent activation of alphaCamKII [9].
• The ability of DHPG to stimulate phosphoinositide (PI) hydrolysis (striatal slices), to influence striatal dopamine release (in vivo microdialysis) and to potentiate the effects of NMDA on extracellular field potential amplitude (extracellular recordings on striatal slices) was reduced in the striatum of old vs young rats [22].

References