Enhanced Activity of Topical Hydrocortisone by Competitive Binding of Corticosteroid-Binding Globulin.

Atopic dermatitis of sensitive areas such as the face, particularly in children, is a difficult disease to treat as the standard therapeutic, topical steroids, is contraindicated for this application in children. Hydrocortisone (HC) can be used in these instances because it has been shown to be safe, but is often ineffective as it is a relatively weak steroid, especially at over-the-counter concentrations. To enhance the local topical activity of HC, the terminal inactive metabolite of prednisolone, Δ(1)-cortienic acid (Δ(1)-CA), is added to HC, as Δ(1)-CA preferentially binds transcortin, liberating more HC to elicit its therapeutic effect.

Delineation of ligand binding and receptor signaling activities of purified P2Y receptors reconstituted with heterotrimeric G proteins.

P2Y receptors are G protein coupled receptors that respond to extracellular nucleotides to promote a multitude of signaling events. Our laboratory has purified several P2Y receptors with the goal of providing molecular insight into their: (1) ligand binding properties, (2) G protein signaling selectivities, and (3) regulation by RGS proteins and other signaling cohorts. The human P2Y(1) receptor and the human P2Y(12) receptor, both of which are intimately involved in ADP-mediated platelet aggregation, were purified to near homogeneity and studied in detail.

Nicotinic acid: pharmacological effects and mechanisms of action.

Pharmacological doses of nicotinic acid induce a profound change in the plasma levels of various lipids and lipoproteins. The ability of nicotinic acid to strongly increase the plasma concentration of high-density lipoprotein (HDL) cholesterol has in recent years led to an increased interest in the pharmacological potential of nicotinic acid. There is increasing evidence that nicotinic acid alone or in addition to LDL cholesterol-lowering drugs can reduce the progression of atherosclerosis and reduce the risk of cardiovascular events.

Structure of Galpha(i1) bound to a GDP-selective peptide provides insight into guanine nucleotide exchange.

Heterotrimeric G proteins are molecular switches that regulate numerous signaling pathways involved in cellular physiology. This characteristic is achieved by the adoption of two principal states: an inactive, GDP bound state and an active, GTP bound state. Under basal conditions, G proteins exist in the inactive, GDP bound state; thus, nucleotide exchange is crucial to the onset of signaling.

C(8)-substituted 1-azabicyclo[3.3.1]non-3-enes: a novel scaffold for muscarinic receptor ligands.

The [3.3.1]-bicyclic amine, exo-8-benzyloxymethyl-3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.

Purification and functional reconstitution of the human P2Y12 receptor.

The human P2Y12 receptor (P2Y12-R) is a member of the G protein coupled P2Y receptor family, which is intimately involved in platelet physiology. We describe here the purification and functional characterization of recombinant P2Y12-R after high-level expression from a baculovirus in Sf9 insect cells. Purified P2Y12-R, Gbeta1gamma2, and various Galpha-subunits were reconstituted in lipid vesicles, and steady-state GTPase activity was quantified.

C(8) substituted 1-azabicyclo[3.3.1]non-3-enes and C(8) substituted 1-azabicyclo[3.3.1]nonan-4-ones: novel muscarinic receptor antagonists.

Expedient syntheses of C(8) substituted 1-azabicyclo[3.3.1]non-3-enes and C(8) substituted 1-azabicyclo[3.

RGS6, RGS7, RGS9, and RGS11 stimulate GTPase activity of Gi family G-proteins with differential selectivity and maximal activity.

Regulator of G-protein signaling (RGS) proteins are GTPase activating proteins (GAPs) of heterotrimeric G-proteins that alter the amplitude and kinetics of receptor-promoted signaling. In this study we defined the G-protein alpha-subunit selectivity of purified Sf9 cell-derived R7 proteins, a subfamily of RGS proteins (RGS6, -7, -9, and -11) containing a Ggamma-like (GGL) domain that mediates dimeric interaction with Gbeta(5). Gbeta(5)/R7 dimers stimulated steady state GTPase activity of Galpha-subunits of the G(i) family, but not of Galpha(q) or Galpha(11), when added to proteoliposomes containing M2 or M1 muscarinic receptor-coupled G-protein heterotrimers.