Molecular and cellular analysis of human histamine receptor subtypes

Abstract

The human histamine receptors hH1R and hH2R constitute important drug targets, and hH3R and hH4R have substantial potential in this area. Considering the species-specificity of pharmacology of HxR orthologs, it is important to analyze hHxRs. Here,we summarize current knowledge of hHxRs endogenously expressed in human cells and hHxRs recombinantly expressed in mammalian and insect cells. We present the advantages and disadvantages of the various systems. We also discuss problems associated with the use of hHxR antibodies, an issue of general relevance for G-protein-coupled receptors (GPCRs). There is much greater overlap in activity of ‘selective’ ligands for other hHxRs than the cognate receptor subtype than generally appreciated. Studies with native and recombinant systems support the concept of ligand-specific receptor conformations, encompassing agonists and antagonists. It is emerging that for characterization of hHxR ligands, one cannot rely on a single test system and a single parameter. Rather, multiple systems and parameters have to be studied. Although such studies are time-consuming and expensive, ultimately, they will increase drug safety and efficacy.

Histamine Intolerance: why freshness matters

“…Within the human body, mast cells, basophils, gastric enterochromaffin cells, histaminergic neurons, and certain gut bacteria all possess the HDC enzyme and are therefore capable of producing histamine. To make matters more complicated, there are four distinct histamine receptor subtypes in the human body: H1, H2, H3 and H4, each with a unique response to histamine binding [6]. Thus, histamine produces different effects on nearby cells, depending on which cell type and receptor it binds to, resulting in a staggering variety of potential physiological responses to its release.…”

Integrative genomic analyses of the histamine H1 receptor and its role in cancer prediction

“…Its various actions are mediated by histamine receptors H1, H2, H3 and H4 (1). The bovine histamine H1 receptor (HRH1) was the first HRH1 gene to be cloned, soon to be followed by other species, including human HRH1.…”

“…The bovine histamine H1 receptor (HRH1) was the first HRH1 gene to be cloned, soon to be followed by other species, including human HRH1. The human HRH1 gene is located on chromosome 3p25 and encodes for a 487 amino acid G protein-coupled receptor (GPCR) with a long third intracellular loop (IL3) (1). The HRH1 predominantly couples to Gα q/11 proteins, leading to the activation of phospholipase C (PLC) and subsequent release of the second messengers inositol trisphosphate (IP 3 ) and diacylglycerol (DAG) followed by the activation of protein kinase C (PKC) and the release of [Ca 2+ ] i (1).…”

“…The human HRH1 gene is located on chromosome 3p25 and encodes for a 487 amino acid G protein-coupled receptor (GPCR) with a long third intracellular loop (IL3) (1). The HRH1 predominantly couples to Gα q/11 proteins, leading to the activation of phospholipase C (PLC) and subsequent release of the second messengers inositol trisphosphate (IP 3 ) and diacylglycerol (DAG) followed by the activation of protein kinase C (PKC) and the release of [Ca 2+ ] i (1). HRH1 is expressed in a wide variety of tissues including the gastrointestinal tract, the central nervous system, the immunological system, and the cardiovascular and genitourinary systems (2)(3)(4)(5).…”

How do basic secretagogues activate mast cells?

“…It is reasonable to assume that both GPCR-dependent and GPCR-independent mechanisms are involved in CAD-induced pseudo-allergy. For 2-phenylhistamines, histamine H 1 -receptor-dependent and H 1 -receptor-independent G-protein-mediated effects have already been documented (Hagelüken et al 1995b;Seifert et al 1994Seifert et al , 2013. Understanding the mechanism of CAD action is not only of academic interest but also of therapeutic relevance because direct G-protein activation is expected to be less accessible to pharmacological intervention than GPCRmediated mechanisms.…”