The C Terminus of the Metabotropic Glutamate Receptor Subtypes 2 and 7 Specifies the Receptor Signaling Pathways

Abstract

There is accumulating evidence that the specificity of the transduction cascades activated by G protein-coupled receptors cannot solely depend on the nature of the coupled G protein. To identify additional structural determinants, we studied two metabotropic glutamate (mGlu) receptors, the mGlu2 and mGlu7 receptors, that are both coupled to G o proteins but are known to affect different effectors in neurons. Thus, the mGlu2 receptor selectively blocks N-and L-type Ca 2؉ channels via a protein kinase C-independent pathway, whereas the mGlu7 receptor selectively blocks P/Q-type Ca 2؉ channels via a protein kinase C-dependent pathway, and both effects are pertussis toxin-sensitive. We examined the role of the C-terminal domain of these receptors in this coupling. Chimeras were constructed by exchanging the C terminus of these receptors and transfected into neurons. Different chimeric receptors bearing the C terminus of mGlu7 receptor blocked selectively P/Qtype Ca 2؉ channels, whereas chimeras bearing the C terminus of mGlu2 receptor selectively blocked N-and L-type Ca 2؉ channels. These results show that the C terminus of mGlu2 and mGlu7 receptors is a key structural determinant that allows these receptors to select a specific signaling pathway in neurons.

Roles of intraloops‐2 and ‐3 and the proximal C‐terminus in signalling pathway selection from the human calcium‐sensing receptor

“…4). The C-terminus also plays important roles in coupling other class C GPCRs to specific G-protein-dependent signalling pathways [34]. For example, alternative splicing of mGluR-1 results in distinct G-protein coupling profiles based on differences in C-terminus sequences.…”

Truncation of the A1 Adenosine Receptor Reveals Distinct Roles of the Membrane-proximal Carboxyl Terminus in Receptor Folding and G Protein Coupling

“…NHERF and activating transcription factor 4 (11,12); hence, the C-tail may support the direct association with effectors, bypassing the cognate G protein. This role was exemplified by comparing the signaling properties of glutamate receptor type II and type VII (13). Both subtypes are G i /G o coupled receptors and they inhibit Ca 2ϩ -currents in neurons but differ in their channel subtype specificity (P/Q-type versus N-and L-type).…”

Identification of a Novel Site within G Protein α Subunits Important for Specificity of Receptor-G Protein Interaction

“…Likewise, the first intracellular loop (Strader et al, 1994(Strader et al, , 1995Ho et al, 2002) or the receptor's C terminal tail (Perroy et al, 2001;Lai et al, 2002) rarely determine coupling specificity. On the level of the G protein ␣ subunit, several different regions have been implicated in recognition of GPCRs and thus determine the specificity of receptor-G protein coupling: the extreme C terminus (Conklin et al, 1993;Kostenis et al, 1997a;Blahos et al, 1998;Havlickova et al, 2003;, the extreme N terminus (Kostenis et al, 1997b;, a region between the ␣4-and ␣5-helices (␣4 -␤6 loop) (Mazzoni and Hamm, 1996;Bae et al, 1997;Onrust et al, 1997;, and a region within the loop linking the N-terminal ␣-helix to the ␤1-strand of the ras-like domain (Blahos et al, 2001).…”