G-protein-coupled receptors for neurotransmitter amino acids: C-terminal tails, crowded signalosomes

G-protein-coupled receptors (GPCRs) represent a superfamily of highly diverse integral membrane proteins that transduce external signals to different subcellular compartments, including nuclei, via trimeric G-proteins. By differential activation of diffusible Galpha and membrane-bound Gbetagamma subunits, GPCRs might act on both cytoplasmic/intracellular and plasma-membrane-bound effector systems. The coupling efficiency and the plasma membrane localization of GPCRs are regulated by a variety of interacting proteins. In this review, we discuss recently disclosed protein interactions found with the cytoplasmic C-terminal tail regions of two types of presynaptic neurotransmitter receptors, the group III metabotropic glutamate receptors and the gamma-aminobutyric acid type-B receptors (GABA(B)Rs). Calmodulin binding to mGluR7 and other group III mGluRs may provide a Ca2+-dependent switch for unidirectional (Galpha) versus bidirectional (Galpha and Gbetagamma) signalling to downstream effector proteins. In addition, clustering of mGluR7 by PICK I (protein interacting with (C) under barC-(k) under bar inase (1) under bar), a polyspecific PDZ ((P) under bar SD-95/(D) under bar lg1/(Z) under barO-1) domain containing synaptic organizer protein, sheds light on how higher-order receptor complexes with regulatory enzymes (or 'signalosomes') could be formed. The interaction of GABA(B)Rs with the adaptor protein 14-3-3 and the transcription factor ATF4 ((a) under bar ctivating (t) under bar ranscription (f) under bar actor (4) under bar) suggests novel regulatory pathways for G-protein signalling, cytoskeletal reorganization and nuclear gene expression: processes that may all contribute to synaptic plasticity.