http://yael-nissan.weebly.com/uploads/5/2/9/2/5292348/the_introduction_to_pain_an_integrative_review_-_millan.pdf

The induction of pain: an integrative review

Kinins are proinflammatory peptides that mediate numerous vascular and pain responses to tissue injury. Two pharmacologically distinct kinin receptor subtypes have been identified and characterized for these peptides, which are named B1 and B2 and belong to the rhodopsin family of G protein-coupled receptors. The B2 receptor mediates the action of bradykinin (BK) and lysyl-bradykinin (Lys-BK), the first set of bioactive kinins formed in response to injury from kininogen precursors through the actions of plasma and tissue kallikreins, whereas the B(1) receptor mediates the action of des-Arg9-BK and Lys-des-Arg9-BK, the second set of bioactive kinins formed through the actions of carboxypeptidases on BK and Lys-BK, respectively. The B2 receptor is ubiquitous and constitutively expressed, whereas the B1 receptor is expressed at a very low level in healthy tissues but induced following injury by various proinflammatory cytokines such as interleukin-1beta. Both receptors act through G alpha(q) to stimulate phospholipase C beta followed by phosphoinositide hydrolysis and intracellular free Ca2+ mobilization and through G alpha(i) to inhibit adenylate cyclase and stimulate the mitogen-activated protein kinase pathways. The use of mice lacking each receptor gene and various specific peptidic and nonpeptidic antagonists have implicated both B1 and B2 receptors as potential therapeutic targets in several pathophysiological events related to inflammation such as pain, sepsis, allergic asthma, rhinitis, and edema, as well as diabetes and cancer. This review is a comprehensive presentation of our current understanding of these receptors in terms of molecular and cell biology, physiology, pharmacology, and involvement in human disease and drug development.

https://pharmrev.aspetjournals.org/content/pharmrev/57/1/27.full.pdf

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

Inositol phospholipid-specific phospholipase C is the enzyme that generates phosphoinositide-derived messenger molecules. Mammalian cells contain at least five immunologically distinct phospholipase C enzymes that appear to be separate gene products. Complete amino acid sequences of four of these isozymes have been established. The overall sequence similarity is surprisingly low for enzymes catalyzing the same chemical reaction: three of them show limited amino acid sequence similarity to each other in two narrow regions, and the fourth enzyme is completely different. The diversity in primary structure together with different regional and cellular expression of the isozymes suggests that each isozyme has a defined function in processing the physiological response of different cell types to a variety of external stimuli and that each is regulated differently.

/pdf/studies-of-inositol-phospholipid-specific-phospholipase-c-4zpez83lk0.pdf

Studies of inositol phospholipid-specific phospholipase C.

Bradykinin receptors: pharmacological properties and biological roles.

Activation of cell-surface receptors by appropriate ligands causes the generation of second messengers which are released in the cell interior. Such transmembrane signalling mechanisms pervade the whole of biology and the classic example is that of cyclic AMP produced as a result of an increase in the activity of an integral membrane enzyme, adenylate cyclase. In this case, receptor stimulation results in the association of the activated receptor with a GTP-binding protein, G., and this, in turn, regulates the activity of adenylate cyclase. The minimum requirement for this signalling cascade is three proteins residing in a single compartment, the plasma membrane with the cytosolic compartment providing the substrate, MgATP for adenylate cyclase. A more recently recognized transmembrane signalling system is the cascade that regulates intracellular Ca2l and protein phosphorylation. This remarkable system where hydrolysis of a phospholipid results in the generation of two second messengers has captured the imagination of many people working in disparate areas such as cell growth and differentiation, plant physiology, phototransduction in invertebrates, and a host of functional responses including contraction, secretion, metabolic responses. In many cases, the inositide signalling pathway is the major controller of subsequent events. The enzyme(s) responsible for hydrolysing the inositol lipid, phosphatidylinositol bisphosphate (PtdInsP2) is a phosphodiesterase of the phospholipase C type. By this we mean that this enzyme is responsible for rupturing the bond between the oxygen and the phosphate such that the products of the reaction are diacylglycerol and the water-soluble headgroup, Ins(1,4,5)P3. Diacylglycerol is responsible for activating a large family of protein kinase C isoenzymes, which catalyse protein phosphorylation. InsP3 on the other hand interacts with a receptor on the endoplasmic recticulum to release Ca2+ from internal stores. This simultaneous generation of two second messengers sets in motion a train of events that results in the culmination of the cellular response. The number of receptors that use this signalling pathway is extensive and what has now emerged is that phospholipase C is regulated by receptors by at least two distinct pathways. The presence of multiple isoforms ofPLC which bear minimal relationship was already a clear indication that differential regulation may occur. Two pathways that have been clearly and unambiguously identified are G-protein-mediated and tyrosine kinase-mediated regulation of PLCs. In this Review we focus on the different isoforms that constitute the phospholipase C family. Several reviews have appeared recently on the enzymology of phospholipase C (see [1-7]) and therefore this review focuses on the recent explosion in our knowledge regarding the regulation of the phospholipases by receptors. For this reason, a number of reconstitution systems have been developed to address this problem. The advantages of different reconstitution systems and their drawbacks will be discussed.

/pdf/inositol-lipid-specific-phospholipase-c-isoenzymes-and-their-24gj35zant.pdf

Inositol-lipid-specific phospholipase C isoenzymes and their differential regulation by receptors.

Bradykinin-activated transmembrane signals are coupled via No or Ni to production of inositol 1,4,5-trisphosphate, a second messenger in NG108-15 neuroblastoma-glioma hybrid cells (GTP-binding proteins/pertussis toxin/adenylate cyclase/ion channels/phosphatidylinositol turnover)

Richard A. STREATYt

Papers

Bradykinin-activated transmembrane signals are coupled via No or Ni to production of inositol 1,4,5-trisphosphate, a second messenger in NG108-15 neuroblastoma-glioma hybrid cells (GTP-binding proteins/pertussis toxin/adenylate cyclase/ion channels/phosphatidylinositol turnover)