Kinin B₁ receptors: key G‐protein‐coupled receptors and their role in inflammatory and painful processes

Abstract

Kinins are a family of peptides implicated in several pathophysiological events. Most of their effects are likely mediated by the activation of two G-protein-coupled receptors: B 1 and B 2 . Whereas B 2 receptors are constitutive entities, B 1 receptors behave as key inducible molecules that may be upregulated under some special circumstances. In this context, several recent reports have investigated the importance of B 1 receptor activation in certain disease models. Furthermore, research on B 1 receptors in the last years has been mainly focused in determining the mechanisms and pathways involved in the process of induction. This was essentially favoured by the advances obtained in molecular biology studies, as well as in the design of selective and stable peptide and nonpeptide kinin B 1 receptor antagonists. Likewise, development of kinin B 1 receptor knockout mice greatly helped to extend the evidence about the relevance of B 1 receptors during pathological states. In the present review, we attempted to remark the main advances achieved in the last 5 years about the participation of kinin B 1 receptors in painful and inflammatory disorders. We have also aimed to point out some groups of chronic diseases, such as diabetes, arthritis, cancer or neuropathic pain, in which the strategic development of nonpeptidic oral-available and selective B 1 receptor antagonists could have a potential relevant therapeutic interest.

Bradykinin-related peptides (BRPs) from skin secretions of three genera of phyllomedusine leaf frogs and their comparative pharmacological effects on mammalian smooth muscles

“…These observations have been explained through receptor coupling to different second messenger pathways in different cells and/or to the presence of different regional profiles of receptor subtype expression [1,17]. In mammals, including humans, the primary structure of BK appears to be invariant as is the presence of two different subtypes of BK receptors, designated B 1 and B 2 [14,15] and both are classical, seven trans-membrane domain, G-protein-linked receptors (GPCRs) [2,11,14,15]. The B 2 receptor is constitutively expressed by many types of cells, including smooth muscle cells, while the B 1 receptor is inducible and is expressed de novo in various cell types after trauma or at sites of chronic inflammation [2,11,14,15].…”

“…In mammals, including humans, the primary structure of BK appears to be invariant as is the presence of two different subtypes of BK receptors, designated B 1 and B 2 [14,15] and both are classical, seven trans-membrane domain, G-protein-linked receptors (GPCRs) [2,11,14,15]. The B 2 receptor is constitutively expressed by many types of cells, including smooth muscle cells, while the B 1 receptor is inducible and is expressed de novo in various cell types after trauma or at sites of chronic inflammation [2,11,14,15]. Each receptor has different ligand structure/activity requirements with BK activating both but with des-(Arg 9 )-BK being the preferential ligand for the B 1 subtype [2,11,14,15].…”

“…The B 2 receptor is constitutively expressed by many types of cells, including smooth muscle cells, while the B 1 receptor is inducible and is expressed de novo in various cell types after trauma or at sites of chronic inflammation [2,11,14,15]. Each receptor has different ligand structure/activity requirements with BK activating both but with des-(Arg 9 )-BK being the preferential ligand for the B 1 subtype [2,11,14,15]. Differentiation of receptors sub-types for discrete peptide ligands usually requires the availability and utilization of fragments and structural analogs of the natural ligand [2,11,14,15].…”

“…The spectrum of BK analogs produced in amphibian defensive skin secretions is unique in Nature and most components have not been comparatively evaluated alongside BK to interrogate the structure/activity requirements of mammalian BK receptors with the view to identifying novel receptors or novel receptor sub-types. The data derived from such comparative studies of ligand potency should be interpreted with caution as some analogs, particularly those with extensions at either N-or C-terminals, may have radically different values due to longer biological half-lives (as a consequence of increased stability to protease attack) or to their requirements for bioactivation through exposure of active, receptor-binding sites [2,9,15,17]. The studies on each smooth muscle type performed in the absence or presence of specific bradykinin B 1 and B 2 receptor antagonists produced additional evidence to interpret the relative myotropic activities obtained in the previous dose-response studies.…”

Expression of the genes encoding kinin receptors are increased in human carotid atherosclerotic plaques

“…Previously, a number of studies have shown the increased expression of B1R and B2R in atherosclerotic vessels and peripheral blood cells of patients with atherosclerosis (11,12). Particularly, in the cardiovascular systems, kinins have been found to be involved in the pathogenesis of heart failure (13).…”