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GTP-Binding Protein alpha Subunits
About: GTP-Binding Protein alpha Subunits is a research topic. Over the lifetime, 304 publications have been published within this topic receiving 19915 citations.
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TL;DR: A combination of G(alpha) affinity chromatography, GTP binding/hydrolysis studies, and genetic analysis allowed us to assign a distinct mechanism of action to each of these mutant proteins.
11 citations
TL;DR: Direct interaction of the BKB2R with both G αi2 and Gαi3 subunits is delineated in addition to the heretofore described interaction of BKB1R with the Gαq subunit family.
11 citations
TL;DR: A series of new molecules characterized by a long hydrophobic chain and at least two nitrogen atoms protonated at physiological pH was designed and synthesized and found to be active, which may be useful leads to develop more potent and selective Gi protein modulators.
Abstract: Heterotrimeric G proteins play a pivotal role in the communication of cells with the environment. G proteins are stimulated by cell surface receptors (GPCR) that catalyze the exchange of GDP, bound to Galpha subunit, with GTP and can per se be the target of drugs. Based on the structure of two nonpeptidic modulators of Gi proteins, a series of new molecules characterized by a long hydrophobic chain and at least two nitrogen atoms protonated at physiological pH was designed. The compounds were tested for their ability to stimulate binding of GTPgammaS to recombinant Gi proteins. Gi activation properties were also evaluated by inhibition of adenylyl cyclase activity in intact lymphocytes. Most compounds were able to stimulate GTPgammaS binding and to inhibit cAMP production at micromolar doses. Among the active compounds, 34 showed good efficacy and was the most potent compound studied, particularly on alpha(o) subtype; its regioisomer, 36, was the most efficacious one. Compound 7 showed also an interesting profile as it showed selectivity toward the alpha(o) subtype, in both efficacy and potency. Some of the compounds synthesized and found to be active may be useful leads to develop more potent and selective Gi protein modulators.
11 citations
TL;DR: Data indicate that Gi(3) activation is required for potentiation of beta(2)-AR stimulation of AC by alpha(2A/D) andalpha(2B)-AR in DDT1-MF2 cells, and partial and full agonists selectively activate G proteins that lead to drug specific effects on effectors.
Abstract: alpha2-Adrenergic receptor (alpha(2)-AR) activation in the pregnant rat myometrium at midterm potentiates beta(2)-AR stimulation of adenylyl cyclase (AC) via Gbetagamma regulation of the type II isoform of adenylyl cyclase. However, at term, alpha(2)-AR activation inhibits beta(2)-AR stimulation of AC. This phenomenon is associated with changes in alpha(2)-AR subtype expression (midterm alpha(2A/D)-AR >> alpha(2B)-AR; term alpha(2B) >or =alpha(2A/D)-AR), without any change in ACII mRNA, suggesting that alpha(2A/D)- and alpha(2B)-AR differentially regulate beta(2)-cAMP production. To address this issue, we have stably expressed the same density of alpha(2A/D)- or alpha(2B)-AR with AC II in DDT1-MF2 cells. Clonidine (partial agonist) increased beta(2)-AR-stimulated cAMP production in alpha(2A/D)-AR-ACII transfectants but inhibited it in alpha(2B)-AR-ACII transfectants. In contrast, epinephrine (full agonist) enhanced beta(2)-stimulated ACII in both alpha(2A)- and alpha(2B)-ACII clonal cell lines. 4-Azidoanilido-[alpha-(32)P]GTP-labeling of activated G proteins indicated that, in alpha(2B)-AR transfectants, clonidine activated only Gi(2), whereas epinephrine, the full agonist, effectively coupled to Gi(2) and Gi(3). Thus, partial and full agonists selectively activate G proteins that lead to drug specific effects on effectors. Moreover, these data indicate that Gi(3) activation is required for potentiation of beta(2)-AR stimulation of AC by alpha(2A/D) and alpha(2B)-AR in DDT1-MF2 cells. This may reflect an issue of the amount of Gbetagamma released upon receptor activation and/or betagamma composition of Gi(3) versus Gi(2).
10 citations
TL;DR: This article describes briefly the discovery of this novel mode of RGS protein modulation in native cardiac myocytes and gives details of the biochemical and electrophysiological assays used for the functional investigation of this modulation.
Abstract: Regulator of G-protein signaling (RGS) proteins are a family of proteins that accelerate intrinsic GTP hydrolysis on alpha subunits of trimeric G proteins They play crucial roles in the physiological regulation of G-protein-mediated cell signaling If RGS proteins were active unrestrictedly, they would completely suppress G-protein-mediated signaling Therefore, it is important to understand how the actions of RGS proteins are regulated under different physiological conditions We have discovered a physiological mode of regulation of a RGS protein in cardiac myocytes The voltage-dependent formation of Ca2+/calmodulin (CaM) facilitated the GTPase activity of RGS proteins by removing intrinsic inhibition mediated by the phospholipid phosphatidylinositol-3,4,5-trisphosphate This modulation of RGS protein action underlies the characteristic "relaxation" behavior of G-protein-gated K+ channels in native cardiac myocytes This article describes briefly the discovery of this novel mode of RGS protein modulation in native cardiac myocytes and then gives details of the biochemical and electrophysiological assays used for the functional investigation of this modulation These assays would be useful for dissecting the physiological modes of action of RGS proteins in controlling G-protein-mediated signaling machinery
10 citations