Interleukin-1-induced Ether-linked Diglycerides Inhibit Calcium-insensitive Protein Kinase C Isotypes IMPLICATIONS FOR GROWTH SENESCENCE

It is hypothesized that inflammatory cytokines and vasoactive peptides stimulate distinct species of diglycerides that differentially regulate protein kinase C isotypes. In published data, we demonstrated that interleukin-1, in contrast to endothelin, selectively generates ether-linked diglyceride species (alkyl, acyl- and alkenyl, acylglycerols) in rat mesangial cells, a smooth muscle-like pericyte in the glomerulus. We now demonstrate both in intact cell and in cell-free preparations that these interleukin-1 receptor-generated ether-linked diglycerides inhibit immunoprecipitated protein kinase C delta and epsilon but not zeta activity. Neither interleukin-1 nor endothelin affect de novo protein expression of these protein kinase C isotypes. As down-regulation of calcium-insensitive protein kinase C isotypes has been linked to antimitogenic activity, we investigated growth arrest as a functional correlate for IL-1-generated ether-linked diglycerides. Cell-permeable ether-linked diglycerides mimic the effects of interleukin-1 to induce a growth-arrested state in both G-protein-linked receptor- and tyrosine kinase receptor-stimulated mesangial cells. This signaling mechanism implicates cytokine receptor-induced ether-linked diglycerides as second messengers that inhibit the bioactivity of calcium-insensitive protein kinase C isotypes resulting in growth arrest

Relating protein pharmacology by ligand chemistry

The identification of protein function based on biological information is an area of intense research. Here we consider a complementary technique that quantitatively groups and relates proteins based on the chemical similarity of their ligands. We began with 65,000 ligands annotated into sets for hundreds of drug targets. The similarity score between each set was calculated using ligand topology. A statistical model was developed to rank the significance of the resulting similarity scores, which are expressed as a minimum spanning tree to map the sets together. Although these maps are connected solely by chemical similarity, biologically sensible clusters nevertheless emerged. Links among unexpected targets also emerged, among them that methadone, emetine and loperamide (Imodium) may antagonize muscarinic M3, α2 adrenergic and neurokinin NK2 receptors, respectively. These predictions were subsequently confirmed experimentally. Relating receptors by ligand chemistry organizes biology to reveal unexpected relationships that may be assayed using the ligands themselves

HL-Histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs

As a result of superior efficacy and overall tolerability, atypical antipsychotic drugs have become the treatment of choice for schizophrenia and related disorders, despite their side effects. Weight gain is a common and potentially serious complication of some antipsychotic drug therapy, and may be accompanied by hyperlipidemia, hypertension and hyperglycemia and, in some extreme cases, diabetic ketoacidosis. The molecular mechanism(s) responsible for antipsychotic drug-induced weight gain are unknown, but have been hypothesized to be because of interactions of antipsychotic drugs with several neurotransmitter receptors, including 5-HT2A and 5-HT2Cserotonin receptors, H1-histamine receptors, α1- and α2-adrenergic receptors, and m3-muscarinic receptors. To determine the receptor(s) likely to be responsible for antipsychotic-drug-induced weight gain, we screened 17 typical and atypical antipsychotic drugs for binding to 12 neurotransmitter receptors. H1-histamine receptor affinities for this group of typical and atypical antipsychotic drugs were significantly correlated with weight gain (Spearman ρ=−0.72; p less than 0.01), as were affinities for α1A adrenergic (ρ=−0.54; p less than 0.05), 5-HT2C (ρ=−0.49; p less than 0.05) and 5-HT6 receptors (ρ=−0.54; p less than 0.05), whereas eight other receptors' affinities were not. A principal components analysis showed that affinities at the H1, α2A, α2B, 5-HT2A, 5-HT2C, and 5-HT6 receptors were most highly correlated with the first principal component, and affinities for the D2, 5-HT1A, and 5-HT7 receptors were most highly correlated with the second principal component. A discriminant functions analysis showed that affinities for the H1 and α1A receptors were most highly correlated with the discriminant function axis. The discriminant function analysis, as well as the affinity for the H1-histamine receptor alone, correctly classified 15 of the 17 drugs into two groups; those that induce weight gain and those that do not. Because centrally acting H1-histamine receptor antagonists are known to induce weight gain with chronic use, and because H1-histamine receptor affinities are positively correlated with weight gain among typical and atypical antipsychotic drugs, it is recommended that the next generation of atypical antipsychotic drugs be screened to avoid H1-histamine receptors