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

Zhaohui Cai, Julie Saugstad, Scott D. Sorensen, Kelly J. Ciombor, Congxiao Zhang, Hervé Schaffhauser, Frantisek Hubalek, Jan Pohl, Robert Duvoisin, P. Jeffrey Conn

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Recent evidence suggests that the functions of presynaptic metabotropic glutamate receptors (mGluRs) are tightly regulated by protein kinases. We previously reported that cAMP-dependent protein kinase (PKA) directly phosphorylates mGluR2 at a single serine residue (Ser843) on the C-terminal tail region of the receptor, and that phosphorylation of this site inhibits coupling of mGluR2 to GTP-binding proteins. This may be the mechanism by which the adenylyl cyclase activator forskolin inhibits presynaptic mGluR2 function at the medial perforant path-dentate gyrus synapse. We now report that PKA also directly phosphorylates several group III mGluRs (mGluR4a, mGluR7a, and mGluR8a), as well as mGluR3 at single conserved serine residues on their C-terminal tails. Furthermore, activation of PKA by forskolin inhibits group III mGluR-mediated responses at glutamatergic synapses in the hippocampus. Interestingly, β-adrenergic receptor activation was found to mimic the inhibitory effect of forskolin on both group II and III mGluRs. These data suggest that a common PKA-dependent mechanism may be involved in regulating the function of multiple presynaptic group II and group III mGluRs. Such regulation is not limited to the pharmacological activation of adenylyl cyclase but can also be elicited by the stimulation of endogenous Gs-coupled receptors, such as β-adrenergic receptors.

Original languageEnglish (US)
Pages (from-to)756-766
Number of pages11
JournalJournal of Neurochemistry
Volume78
Issue number4
DOIs
StatePublished - 2001
Externally publishedYes

Fingerprint

Presynaptic Receptors
Metabotropic Glutamate Receptors
Cyclic AMP-Dependent Protein Kinases
Protein Kinases
Colforsin
Chemical activation
Adenylyl Cyclases
Synapses
Adrenergic Receptors
Serine
Perforant Pathway
Phosphorylation
Dentate Gyrus
GTP-Binding Proteins
Hippocampus
Pharmacology
metabotropic glutamate receptor 2

Keywords

  • β-adrenergic
  • cAMP-dependent protein kinase
  • mGluR4
  • mGluR7
  • mGluR8
  • Phosphorylation

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Cyclic AMP-dependent protein kinase phosphorylates group III metabotropic glutamate receptors and inhibits their function as presynaptic receptors. / Cai, Zhaohui; Saugstad, Julie; Sorensen, Scott D.; Ciombor, Kelly J.; Zhang, Congxiao; Schaffhauser, Hervé; Hubalek, Frantisek; Pohl, Jan; Duvoisin, Robert; Jeffrey Conn, P.

In: Journal of Neurochemistry, Vol. 78, No. 4, 2001, p. 756-766.

Research output: Contribution to journalArticle

Cai, Zhaohui ; Saugstad, Julie ; Sorensen, Scott D. ; Ciombor, Kelly J. ; Zhang, Congxiao ; Schaffhauser, Hervé ; Hubalek, Frantisek ; Pohl, Jan ; Duvoisin, Robert ; Jeffrey Conn, P. / Cyclic AMP-dependent protein kinase phosphorylates group III metabotropic glutamate receptors and inhibits their function as presynaptic receptors. In: Journal of Neurochemistry. 2001 ; Vol. 78, No. 4. pp. 756-766.
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AU - Cai, Zhaohui

AU - Saugstad, Julie

AU - Sorensen, Scott D.

AU - Ciombor, Kelly J.

AU - Zhang, Congxiao

AU - Schaffhauser, Hervé

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AU - Pohl, Jan

AU - Duvoisin, Robert

AU - Jeffrey Conn, P.

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AB - Recent evidence suggests that the functions of presynaptic metabotropic glutamate receptors (mGluRs) are tightly regulated by protein kinases. We previously reported that cAMP-dependent protein kinase (PKA) directly phosphorylates mGluR2 at a single serine residue (Ser843) on the C-terminal tail region of the receptor, and that phosphorylation of this site inhibits coupling of mGluR2 to GTP-binding proteins. This may be the mechanism by which the adenylyl cyclase activator forskolin inhibits presynaptic mGluR2 function at the medial perforant path-dentate gyrus synapse. We now report that PKA also directly phosphorylates several group III mGluRs (mGluR4a, mGluR7a, and mGluR8a), as well as mGluR3 at single conserved serine residues on their C-terminal tails. Furthermore, activation of PKA by forskolin inhibits group III mGluR-mediated responses at glutamatergic synapses in the hippocampus. Interestingly, β-adrenergic receptor activation was found to mimic the inhibitory effect of forskolin on both group II and III mGluRs. These data suggest that a common PKA-dependent mechanism may be involved in regulating the function of multiple presynaptic group II and group III mGluRs. Such regulation is not limited to the pharmacological activation of adenylyl cyclase but can also be elicited by the stimulation of endogenous Gs-coupled receptors, such as β-adrenergic receptors.

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