Phosphorylation and regulation of group II metabotropic glutamate receptors (mGlu2/3) in neurons

Abstract

Group II metabotropic glutamate (mGlu) receptors (mGlu2/3) are Gαi/o-coupled receptors and are primarily located on presynaptic axonal terminals in the central nervous system. Like ionotropic glutamate receptors, group II mGlu receptors are subject to regulation by posttranslational phosphorylation. Pharmacological evidence suggests that several serine/threonine protein kinases possess the ability to regulate mGlu2/3 receptors. Detailed mapping of phosphorylation residues has revealed that protein kinase A (PKA) phosphorylates mGlu2/3 receptors at a specific serine site on their intracellular C-terminal tails in heterologous cells or neurons, which underlies physiological modulation of mGlu2/3 signaling. Casein kinases promote mGlu2 phosphorylation at a specific site. Tyrosine protein kinases also target group II receptors to induce robust phosphorylation. A protein phosphatase was found to specifically bind to mGlu3 receptors and dephosphorylate the receptor at a PKA-sensitive site. This review summarizes recent progress in research on group II receptor phosphorylation and the phosphorylation-dependent regulation of group II receptor functions. We further explore the potential linkage of mGlu2/3 phosphorylation to various neurological and neuropsychiatric disorders, and discuss future research aimed at analyzing novel biochemical and physiological properties of mGlu2/3 phosphorylation.

Keywords: PKA; PKC; casein kinase; glutamate; mGlu; phosphatase; phosphorylation.

FIGURE 1

Schematic illustration of transmembrane topology of rat mGlu2 receptors. The illustrated regions include seven transmembrane domains (I-VII) and four intracellular domains, i.e., the intracellular loop 1 (IL1), IL2, IL3, and C-terminus (CT). Amino acid sequences of intracellular domains are labeled by the single letter code (accession #: NP_001099181/NCBI; P31421/UniProtKB). Note that all intracellular domains contain serine and/or threonine but not tyrosine residues. Solid circles indicate the serine sites where variable levels of phosphorylation have been detected. Other abbreviations: CK1, casein kinase 1; NT, N-terminus; PKA, protein kinase A.

FIGURE 2

Alignment of amino acid sequences of intracellular domains between mGlu2 and mGlu3 subtypes and among three species. (A) Sequence alignment of intracellular domains between mGlu2 versus mGlu3 receptors. Intracellular domains include the intracellular loop 1 (IL1), IL2, IL3, and C-terminus (CT). Gaps (–) are inserted in the mGlu3 CT region to achieve maximum homolog. Note that the mGlu3 CT region contains two tyrosine residues (Y853 and Y861) indicated by solid triangles. (B) Sequence alignment of the CT regions among human, mouse, and rat mGlu2 orthologs. Note that the S843 residue is conserved in the three species. Underlined amino acids denote differences in sequence alignment. Open boxes indicate CaMKII consensus phosphorylation sequences.

FIGURE 3

Phosphorylation and dephosphorylation of mGlu3 receptors. (A) Dephosphorylation of mGlu3 receptors by PP2C. PP2C dephosphorylates mGlu3 receptors at a specific serine residue (S845) in the C-terminus (CT) region of the receptor. (B) Phosphorylation of mGlu3 receptors by PKA. PKA phosphorylates mGlu3 receptors at S845 and increases the level of S845-phosphorylated (pS845) mGlu3 receptors. Such phosphorylation inhibits the PP2C association with mGlu3 CT and may exert an inhibitory control over the presynaptic function of mGlu3 receptors.