Norma P. Gerard

Neutral Endopeptidase Modulates Septic Shocka

Neutral endopeptidase (NEP; EC 3.4.24.11) is a type-2 cell-surface metalloproteinase known by a variety of eponyms, including enkephalinase, common acute lymphoblastic leukemia antigen (CALLA), and CD10. Identified substrates are largely neural or humoral oligopeptide agonists, and the enzyme functions to terminate signaling by degrading the ligand, analogous to the acetylcholine/acetylcholinesterase system. Targeted disruption of the NEP locus in mice results in enhanced lethality to endotoxin shock with a pronounced gene-dosage effect. The site(s) of action appears downstream from release of TNF and IL-1, as NEP-deficient animals demonstrate increased sensitivity to these mediators as well. This unexpected finding indicates an important protective role for NEP in septic shock.

Chapter 2.3 – Chemokine Receptors

Publisher Summary nThe chapter provides an overview of chemokine receptor classication, genomic location, structure, expression, binding, function, viral mimics, therapeutic implications, and potential decoy receptors. It discusses a hypothesis that the chemokine system, like the IL-1 pathway, has endogenous decoy receptors in addition to the Duffy antigen. Understanding the multifaceted roles of chemokines and their receptors in vivo has been facilitated by the development of transgenic mice and targeted deletion/mutagenesis of chemokines and their receptors. Chemokines are subdivided into classes based on the relative positions of their N-terminal cysteine residues. Chemokine receptors have a structure similar to that of other G protein-coupled receptors. The structure of chemokine receptors is characteristic of receptors, such as rhodopsin and the muscarinic acetylcholine receptor, which are coupled with guanine nucleotide binding proteins (G proteins). Chemokine receptor expression varies with cell type and receptor. Some receptors are restricted to certain cell types while others are expressed on many cell types. Chemokine receptors play a major role in two infectious diseases that cause significant morbidity and mortality worldwide: human immunodeciency virus (HIV) and malaria. One of the accepted models for chemokine/chemokine receptor interaction is the two-step binding and signaling model. In this model, the chemokine binds to the initial binding site, and the ensuing conformational change allows the pharmacophore to interact with the transmembrane helices to trigger signal transduction.