Mapping of calmodulin and G beta gamma binding domains within the C-terminal region of the metabotropic glutamate receptor 7A

Far, O., Bofill-Cardona, E., Airas, J.M., Connor, V., Boehm, S., Freissmuth, M., Nanoff, C. and Betz, H. (2001) Mapping of calmodulin and G beta gamma binding domains within the C-terminal region of the metabotropic glutamate receptor 7A. The Journal of Biological Chemistry, 276 (33), 30662-30669. (doi:10.1074/jbc.M102573200).

Abstract

Ca2+/calmodulin (Ca2+/CaM) and the subunits of heterotrimeric G-proteins (G) have recently been shown to interact in a mutually exclusive fashion with the intracellular C terminus of the presynaptic metabotropic glutamate receptor 7 (mGluR 7). Here, we further characterized the core CaM and G binding sequences. In contrast to a previous report, we find that the CaM binding motif localized in the N-terminal region of the cytoplasmic tail domain of mGluR 7 is conserved in the related group III mGluRs 4A and 8 and allows these receptors to also bind Ca2+/CaM. Mutational analysis of the Ca2+/CaM binding motif is consistent with group III receptors containing a conventional CaM binding site formed by an amphipathic -helix. Substitutions adjacent to the core CaM target sequence selectively prevent G binding, suggesting that the CaM-dependent regulation of signal transduction involves determinants that overlap with but are different from those mediating G recruitment. In addition, we present evidence that G uses distinct nonoverlapping interfaces for interaction with the mGluR 7 C-terminal tail and the effector enzyme adenylyl cyclase II, respectively. Although G-mediated signaling is abolished in receptors lacking the core CaM binding sequence, subunit activation, as assayed by agonist-dependent GTPS binding, was not affected. This suggests that Ca2+/CaM may alter the mode of group III mGluR signaling from mono- () to bidirectional ( and ) activation of downstream effector cascades.

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