Cyclic AMP‐dependent protein kinase phosphorylates group III metabotropic glutamate receptors and inhibits their function as presynaptic receptors

Cai, Zhaohui; Saugstad, Julie A.; Sorensen, Scott D.; Ciombor, Kelly J.; Zhang, Congxiao; Schaffhauser, Hervé; Hubálek, František; Pohl, Jan; Duvoisin, Robert M.; Conn, P. Jeffrey

doi:10.1046/j.1471-4159.2001.00468.x

Cited by 54 publications

(76 citation statements)

References 47 publications

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“…This 20-aa region between residues 836 and 855 corresponds to the part of the cytoplasmic domain of mGluR3 that is not conserved between mGluR3 and mGluR2. The C-terminal cytoplasmic tails of several mGluRs are phosphorylated, with both mGluR2 and mGluR3 being phosphorylated by PKA at distinct sites within the nonconserved region (20,21). We confirmed that Ser-845, situated within residues 836-855 of mGluR3, was an effective substrate for PKA in vitro.…”

Section: Discussionsupporting

confidence: 61%

“…The cleaved polypeptide was efficiently phosphorylated in vitro by PKA (see also ref. 20), and mutation of Ser-845 to Ala or Asp abolished phosphorylation (data not shown).…”

Section: Identification Of Pp2c As An Mglur3-interacting Protein By Umentioning

confidence: 84%

“…In contrast, mGluR2 would not be subject to the same type of regulation. Phosphorylation of mGluR2 by PKA has been shown to inhibit mGluR2͞G protein coupling and attenuate its function as a presynaptic receptor (20,31). Given the close relationship between mGluR2 and mGluR3, it is possible that phosphorylation by PKA also limits signaling by mGluR3.…”

Section: Discussionmentioning

confidence: 99%

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Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3

Flajolet

Rakhilin

Wang

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Cell surface receptor membrane localization is strongly dependent on protein-protein interactions often involving regulation by phosphorylation͞dephosphorylation of the intracellular domains of membrane proteins. The present study was carried out to identify metabotropic glutamate receptor (mGluR) 3 regulatory binding proteins. Using the yeast two-hybrid technique, we found that the 50-aa C-terminal cytoplasmic tail of mGluR3 interacts specifically with protein phosphatase 2C␣ (PP2C␣). This interaction was confirmed by GST pull-down and coimmunoprecipitation assays. mGluR3 interacts with PP2C␣, ␤, ␥, and ␦ isoforms; however, among the mGluR family only mGluR3 interacted with PP2C. The minimal interacting domain of mGluR3 comprised residues 836 -855. Alignment between mGluR3 and mGluR2, a closely related group II receptor, indicated that this domain is not conserved between the two receptors. The mGluR3 cytoplasmic C-terminal tail contains one phosphorylation site for protein kinase A (Ser-845), but the phosphatase that dephosphorylates this site has not been previously identified. We find that PP2C, but not PP1, PP2A, or PP2B, dephosphorylates the mGluR3 cytoplasmic tail in vitro. The dephosphorylated form of the mGluR3 cytoplasmic tail, but not the equivalent region of mGluR2, inhibited PP2C assayed by using [ 32 P]casein as a substrate. However, phosphorylation of the mGluR3 cytoplasmic tail at Ser-845 inhibits the interaction with PP2C. These results indicate distinct functions for mGluR2 and mGluR3 and suggest a dynamic regulation of mGluR3 by PP2C.T he vast majority of excitatory synapses in the mammalian central nervous system use the neurotransmitter glutamate to activate two different receptor groups, namely the ''ionotropic'' and the ''metabotropic'' glutamate receptor families. Although ionotropic stimulation is commonly associated with fast neurotransmission, metabotropic glutamate receptor (mGluR) activation drives slower and longer-lasting events. The metabotropic receptor family is divided into three groups based on pharmacological properties, sequence homology, and coupling to intracellular messengers. Group I receptors (mGluR1 and -5) are positively coupled to phospholipase C, whereas group II (mGluR2 and -3) and group III (mGluR4, receptors are negatively coupled to adenylyl cyclase. mGluRs are expressed in most areas of the brain, and extensive data show their importance in major CNS functions and especially neuroplasticity (1, 2). In addition, mGluRs are emerging as new therapeutic targets for neurodegenerative diseases and addiction (3). A variety of drugs acting on group II mGluRs, for instance, have therapeutic potential in the treatment of anxiety, Parkinson disease, schizophrenia, and drug addiction (for reviews, see refs. 4-6).The important role of group II mGluRs in synaptic plasticity, especially in long-term depression, has been extensively characterized (7-9). However, basic and specific properties of group II mGluRs, such as the modulation of glutamate release, origin (vesicular or ...

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Section: Discussionsupporting

confidence: 61%

“…The cleaved polypeptide was efficiently phosphorylated in vitro by PKA (see also ref. 20), and mutation of Ser-845 to Ala or Asp abolished phosphorylation (data not shown).…”

Section: Identification Of Pp2c As An Mglur3-interacting Protein By Umentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3

Flajolet

Rakhilin

Wang

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…Group III mGluRs are known to inhibit G-protein-mediated increase in intracellular cAMP and adenylyl cyclase (Con and Pin 1997). This mechanism was shown to mediate a presynaptic inhibition of glutamate release by group III mGluRs (Cai et al 2001). We suspect a similar action in the postsynaptic sites of neocortical inhibitory circuits that has not yet been reported.…”

Section: Discussionmentioning

confidence: 64%

Differential Metabotropic Glutamate Receptor Expression and Modulation in Two Neocortical Inhibitory Networks

Sun

Zhang

Jiao

et al. 2009

Journal of Neurophysiology

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. Differential metabotropic glutamate receptor expression and modulation in two neocortical inhibitory networks. J Neurophysiol 101: 2679 -2692, 2009. First published February 25, 2009 doi:10.1152/jn.90566.2008. Taking advantage of transgenic mice with genetically labeled GABAreleasing interneurons, we examined the cell-specific patterns of mGluR expression in two broadly defined subtypes of inhibitory interneurons in layer IV of somatosensory cortex. Electrophysiological recording combined with application of specific agonists for specific mGluRs demonstrated different effects of mGluR activation in fast-spiking (FS) versus regular spiking nonpyramidal (RSNP) interneurons. Whereas activation of group I, II, and III mGluRs inhibited excitatory synaptic transmission in RSNP neurons predominantly via postsynaptic mechanisms, group I mGluR activation depolarized FS but not RSNP interneurons. Immunoreactivities of mGluR1, mGluR5, mGluR2/3, and mGluR8 exhibited different cellular expression patterns in the two groups of neurons that were not entirely consistent with physiological and pharmacological experiments. Taken together, our data indicate cell and circuit-specific roles for mGluRs in modulating inhibitory circuits in the somatosensory cortex. These results help to reinforce the concept that RSNP and FS cells represent morphologically, physiologically, and functionally distinct groups of interneurons. The results reported here help to increase our understanding of the roles of mGluRs in endogenous glutamatergic-induced plasticity of interneuronal networks.

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“…However, a1 ARs could exist anywhere at the synapse in BNST, including being present at multiple locations, allowing for other mechanisms of mGluR8 disruption by a1 ARs. Alternatively, in the hippocampus, presynaptic group III mGluRs, including mGluR8 specifically, can be inhibited through phosphorylation by PKA (Cai et al, 2001). Thus, any receptor feeding into the cAMP/PKA pathway could desensitize mGluR8.…”

Section: Discussionmentioning

confidence: 99%

mGluR8 Modulates Excitatory Transmission in the Bed Nucleus of the Stria Terminalis in a Stress-Dependent Manner

Gosnell

Silberman

Grueter

et al. 2011

Neuropsychopharmacol

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Metabotropic glutamate receptors (mGluRs) are important modulators of excitatory transmission, and have been implicated in anxiety and stress-related behaviors. Previously, we showed that group III mGluR agonists could depress excitatory synaptic transmission in the bed nucleus of the stria terminalis (BNST), an integral component of the anxiety circuitry. Here, we provide converging evidence indicating that this effect is mediated primarily by mGluR8, is exerted presynaptically, and is modulated by noradrenergic signaling and stress. The effects of the group III mGluR agonist L-AP4 on excitatory transmission are not potentiated by the mGluR4-selective allosteric potentiator PHCCC, but are mimicked by the mGluR8-selective agonist DCPG. Consistent with these results, mGluR8-like immunoreactivity is seen in the BNST, and the actions of L-AP4 on excitatory transmission are absent in slices from mGluR8 knockout (KO) mice. Application of DCPG is associated with an increase in paired-pulse evoked glutamate synaptic currents, and a decrease in spontaneous glutamate synaptic current frequency, consistent with a primarily presynaptic action. mGluR8-mediated suppression of excitatory transmission is disrupted ex vivo by activation of a1 adrenergic receptors (a1 ARs). BNST mGluR8 function is also disrupted by both acute and chronic in vivo exposure to restraint stress, and in brain slices from a2A AR KO mice. These studies show that mGluR8 is an important regulator of excitatory transmission in the BNST, and suggest that this receptor is selectively disrupted by noradrenergic signaling and by both acute and chronic stress.

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Cyclic AMP‐dependent protein kinase phosphorylates group III metabotropic glutamate receptors and inhibits their function as presynaptic receptors

Cited by 54 publications

References 47 publications

Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3

Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3

Differential Metabotropic Glutamate Receptor Expression and Modulation in Two Neocortical Inhibitory Networks

mGluR8 Modulates Excitatory Transmission in the Bed Nucleus of the Stria Terminalis in a Stress-Dependent Manner

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