Current Mechanistic and Pharmacodynamic Understanding of Melanocortin-4 Receptor Activation

In this work we summarize our understanding of melanocortin 4 receptor (MC4R) pathway activation, aiming to define a safe and effective therapeutic targeting strategy for the MC4R. Delineation of cellular MC4R pathways has provided evidence for distinct MC4R signaling events characterized by unique receptor activation kinetics. While these studies remain narrow in scope, and have largely been explored with peptidic agonists, the results provide a possible correlation between distinct ligand groups and differential MC4R activation kinetics. In addition, when a set of small-molecule and peptide MC4R agonists are compared, evidence of biased signaling has been reported. The results of such mechanistic studies are discussed

Molecular cloning and characterization of a new receptor for galanin

AbstractGalanin (GAL) is a widely distributed neuropeptide with diverse biological effects including modulation of hormone release, antinociception and modification of feeding behavior. Its effects are mediated through G-protein-coupled receptors (GPCR) for which only a single type has been cloned, GAL receptor 1 (GALR1). We describe the cloning of a second galanin receptor type, GALR2, from rat hypothalamus. The GALR2 amino acid sequence is 38% identical to GALR1 and is pharmacologically similar to GALR1 when expressed in COS-7 cells. GALR2 is encoded by a single gene containing at least one intron and expressed in a diverse range of tissues

Resistance to fever induction and impaired acute-phase response in interleukin-1β-deficient mice

AbstractWe used gene targeting in embryonic stem cells to introduce an IL-1β null allele in mice. The IL-1β-deficient mice develop normally and are apparently healthy and fertile. The IL-1β null mice responded normally in models of contact and delayed-type hypersensitivity or following bacterial endotoxin LPS-induced inflammation. The IL-1β-deficlent mice showed equivalent resistance to Listeria monocytogenes compared with wild-type controls. In contrast, when challenged with turpentine, which causes localized inflammation and tissue injury, the IL-1β mutant mice exhibited an impaired acute-phase inflammatory response and were completely resistant to fever development and anorexia. These results highlight a central role for IL-1β as a pyrogen and a mediator of the acute-phase response in a subset of Inflammatory disease models, and support the notion that blocking the action of a single key cytokine can alter the course of specific immune and inflammatory responses