Electrophysiology-based analysis of human histamine H(4) receptor pharmacology using GIRK channel coupling in Xenopus oocytes.
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.
Sahlholm
Kristoffer
K
Department of Neuroscience, Karolinska Institutet, SE-117 77 Stockholm, Sweden.
Nilsson
Johanna
J
Marcellino
Daniel
D
Fuxe
Kjell
K
Arhem
Peter
P
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
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