title: Electrophysiology-based analysis of human histamine H(4) receptor pharmacology using GIRK channel coupling in Xenopus oocytes.
abstract: The recently cloned histamine H(4) receptor is expressed predominantly in haematopoietic cells and has been found to modulate the function of mast cells, eosinophils, dendritic cells and T lymphocytes. It represents an attractive target for pharmacological interventions against a number of inflammatory and autoimmune disorders. In the present work we used two-electrode voltage-clamp to demonstrate histamine H(4) receptor modulation of G protein-coupled inward rectifier potassium (GIRK) channels heterologously expressed in Xenopus oocytes. In accordance with earlier findings in other effector systems, full agonism by histamine and (R)-alpha-methylhistamine, partial agonism by clobenpropit and inverse agonism by thioperamide were observed. Furthermore, in oocytes injected with low amounts of receptor cRNA, clobenpropit apparently acted as a neutral antagonist. We also used the high temporal resolution afforded by this system to study the differential time courses of response deactivation upon ligand washout for clobenpropit and (R)-alpha-methylhistamine. GIRK channels represent a novel effector system for histamine H(4) receptor modulation, which may be of physiological relevance and prove useful in the development of compounds targeting this receptor.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, SE-117 77 Stockholm, Sweden.
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Sahlholm
authors.forename: Johanna
authors.initials: J
authors.lastname: Nilsson
authors.forename: Daniel
authors.initials: D
authors.lastname: Marcellino
authors.forename: Kjell
authors.initials: K
authors.lastname: Fuxe
authors.forename: Peter
authors.initials: P
authors.lastname: Arhem
mesh_terms: D000818:Animals; D004594:Electrophysiology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism*; D017442:Histamine Agonists / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008761:Methylhistamines / Q000494:pharmacology; D009865:Oocytes / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism*; D011968:Receptors, Histamine / Q000187:drug effects / Q000378:metabolism*; D000074040:Receptors, Histamine H4; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014981:Xenopus
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C418607:HRH4 protein, human; D017442:Histamine Agonists; D006633:Histamine Antagonists; D007093:Imidazoles; D008761:Methylhistamines; D010880:Piperidines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C069357:alpha-methylhistamine; D013890:Thiourea; C052075:thioperamide; C086108:clobenpropit