Dissociation of protein kinase-mediated regulation of metabotropic glutamate receptor 7 (mGluR7) interactions with calmodulin and regulation of mGluR7 function

Scott D. Sorensen, Thomas A. Macek, Zhaohui Cai, Julie Saugstad, P. Jeffrey Conn

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Presynaptic metabotropic glutamate receptors (mGluRs) often act as feedback inhibitors of synaptic transmission and serve important roles in defining the activity of glutamatergic synapses. Recent investigations have begun to identify novel interactions of presynaptic mGluRs, especially mGluR7, with multiple protein kinases and putative regulatory proteins that probably serve to further shape the overall activity of glutamatergic synapses. In the present study, we report that in addition to protein kinase C (PKC), cAMP-dependent protein kinase (PKA) and cGMP-dependent protein kinase (PKG) can inhibit calmodulin (CaM) interactions with the carboxyl-terminal tail of mGluR7. These actions are mediated by PKC-, PKA-, or PKG-dependent phosphorylation of mGluR7 at a single serine residue, Ser 862, in the carboxyl terminus of the receptor. Mutation of this residue inhibits kinase-mediated phosphorylation of the mGluR7 carboxyl terminus and reverses kinase-mediated inhibition of CaM binding to mGluR7. However, PKC-mediated inhibition of the functional coupling of mGluR7 to G protein-coupled inward rectifier potassium (GIRK) currents in a heterologous expression system is not affected by mutating Ser 862. Furthermore, mutation of Ser 862 to glutamate to mimic receptor phosphorylation and inhibit CaM interactions with mGluR7 does not affect receptor function. These studies demonstrate that the ability of these second messenger-dependent kinases to inhibit mGluR7-mediated activation of GIRK current is not dependent on the phosphorylation of Ser 862 or the regulation of CaM binding to mGluR7. Furthermore, our studies suggest that CaM binding is not required for mGluR7-mediated activation of GIRK current.

Original languageEnglish (US)
Pages (from-to)1303-1312
Number of pages10
JournalMolecular Pharmacology
Volume61
Issue number6
DOIs
StatePublished - 2002
Externally publishedYes

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Calmodulin
Protein Kinases
Phosphorylation
Metabotropic Glutamate Receptors
Phosphotransferases
Synapses
Protein Kinase C
metabotropic glutamate receptor 7
Cyclic GMP-Dependent Protein Kinases
Mutation
Second Messenger Systems
Cyclic AMP-Dependent Protein Kinases
GTP-Binding Proteins
Synaptic Transmission
Serine
Glutamic Acid
Potassium

ASJC Scopus subject areas

  • Pharmacology

Cite this

Dissociation of protein kinase-mediated regulation of metabotropic glutamate receptor 7 (mGluR7) interactions with calmodulin and regulation of mGluR7 function. / Sorensen, Scott D.; Macek, Thomas A.; Cai, Zhaohui; Saugstad, Julie; Jeffrey Conn, P.

In: Molecular Pharmacology, Vol. 61, No. 6, 2002, p. 1303-1312.

Research output: Contribution to journalArticle

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