Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P19086 (Galphaz)
 110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metabotropic glutamate (mGlu), Ca2+-sensing, gamma-aminobutyric acidB, and a large number of pheromone receptors constitute a peculiar family of G protein-coupled receptors. They possess a large extracellular domain that has been proposed to constitute their ligand binding domain. The aim of the current study was to examine whether this large ligand binding domain had any influence on the G protein-coupling selectivity of the receptor, and vice versa. We chose mGlu receptors, which are classified into three groups according to their sequence homology and pharmacology, as representatives of this receptor family. To define a G protein-coupling profile for these receptors, we used a set of exogenous phospholipase C-activating G proteins in the same way that synthetic ligands are used to define agonist and antagonist pharmacological profiles. This set includes Galpha15, Galpha16, Galphaq, and chimeric Galphaq proteins with the last few amino acids of either Galphai2 (Galphaqi), Galphao (Galphaqo), or Galphaz (Galphaqz). Cotransfection of mGlu receptors with these G proteins and examination of their coupling to phospholipase C revealed that group I, II, and III receptors have distinct G protein-coupling profiles. By swapping the extracellular domains of the most distantly related mGlu receptors (the rat group I mGlu1a and the Drosophila melanogaster group II DmGluA receptors), we show that the extracellular domain determines the agonist pharmacological profile and that this domain does not modify the G protein-coupling profile determined by the seven-transmembrane-domain region of mGlu receptors.
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PMID:The G protein-coupling profile of metabotropic glutamate receptors, as determined with exogenous G proteins, is independent of their ligand recognition domain. 954 71

Metabotropic glutamate receptors (mGlu receptors), the Ca2+-sensing receptor, gamma-aminobutyric acid type B receptors, and one group of pheromone receptors constitute a unique family (also called family 3) of heptahelical receptors. This original family shares no sequence similarity with any other G protein-coupled receptors. The identification and comparison of the molecular determinants of receptor/G protein coupling within the different receptor families may help identify general rules involved in this protein/protein interaction. In order to detect possible contact sites important for coupling selectivity between family 3 receptors and the G protein alpha-subunits, we examined the coupling of the cyclase-inhibiting mGlu2 and mGlu4 receptors to chimeric alphaq-subunits bearing the 5 extreme C-terminal amino acid residues of either Galphai, Galphao, or Galphaz. Whereas mGlu4 receptor activated all three chimeric G proteins, mGlu2 receptor activated Galphaqi and Galphaqo but not Galphaqz. The mutation of isoleucine -4 of Galphaqz into cysteine was sufficient to recover coupling of the mutant G protein to mGlu2 receptor. Moreover, the mutation of cysteine -4 of Galphaqo into isoleucine was sufficient to suppress the coupling to mGlu2 receptor. Mutations at positions -5 and -1 had an effect on coupling efficiency, but not selectivity. Our results emphasize the importance of the residue -4 of the alpha-subunits in their specific interaction to heptahelical receptors by extending this finding on the third family of G protein-coupled receptors.
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PMID:Extreme C terminus of G protein alpha-subunits contains a site that discriminates between Gi-coupled metabotropic glutamate receptors. 974 47

There is a certain cross-talk in the nervous system between N-methyl-D-aspartate receptors (NMDARs) and Mu-opioid receptors (MORs). While NMDARs participate in the desensitization of MORs, these in turn modulate NMDAR-mediated glutamate responses. The G protein coupled receptors (GPCRs) activate NMDARs via Src although the role of Galpha subunits in this process is not well defined. We have found that in the absence of MOR activation, the brain specific Galphaz subunit binds to and stabilizes Src in its inactive form. The administration of morphine provokes the phosphorylation of specific cytosolic tyrosine residues in NMDAR2A subunits. This was achieved by PKCgamma disrupting this Galphaz-Src complex, enabling Src to be activated (pTyr416) by binding to GalphaiGTP proteins. These changes increased the activation of the calcium/calmodulin-dependent protein kinase II (CaMKII), thereby promoting MOR desensitization. This regulatory pathway is disrupted by inhibiting PKC, preventing MOR-activated Galphai2 subunits from gaining control over Src. Thus, in neural cells the Galphaz subunits exert a negative control on Src function reducing the activating influence of MORs on this tyrosine kinase. This MOR-triggered signaling pathway recruits PKCgamma and Galphai subunits to activate Src tyrosine kinase, resulting in the potentiation of NMDAR function. Most relevant, this mechanism which operates in neural cells is essential for the development of tolerance to the analgesic effects of morphine.
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PMID:Brain-specific Galphaz interacts with Src tyrosine kinase to regulate Mu-opioid receptor-NMDAR signaling pathway. 1944 22