Craig Gerard

Neurokinin-1 (NK-1) receptor is required in antigen-induced cystitis.

Interstitial cystitis (IC) is a debilitating disease that has been adversely affecting the quality of womens lives for many years. The trigger in IC is not entirely known, and a role for the sensory nerves in its pathogenesis has been suggested. In addition to inflammation, increased mast cell numbers in the detrusor muscle have been reported in a subset of IC patients. Experimentally, several lines of evidence support a central role for substance P and neurokinin-1 (NK-1) receptors in cystitis. The availability of mice genetically deficient in neurokinin-1 receptor (NK-1R(-/-)) allows us to directly evaluate the importance of substance P in cystitis. An unexpected finding of this investigation is that NK-1R(-/-) mice present increased numbers of mast cells in the bladder when compared with wild-type control mice. Despite the increase in mast cell numbers, no concomitant inflammation was observed. In addition, bladder instillation of wild-type mice with a sensitizing antigen induces activation of mast cells and an acute inflammatory response characterized by plasma extravasation, edema, and migration of neutrophils. Antigen-sensitized NK-1R(-/-) mice also exhibit bladder mast cell degranulation in response to antigen challenge. However, NK-1R(-/-) mice are protected from inflammation, failing to present bladder inflammatory cell infiltrate or edema in response to antigen challenge. This work presents the first evidence of participation of NK-1 receptors in cystitis and a mandatory participation of these receptors on the chain of events linking mast cell degranulation and inflammation.

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.