title: Voltage sensitivities and deactivation kinetics of histamine H₃ and H₄ receptors.
abstract: Agonist potency at some neurotransmitter receptors has been shown to be regulated by voltage, a mechanism which has been suggested to play a crucial role in the regulation of neurotransmitter release by inhibitory autoreceptors. Likewise, receptor deactivation rates upon agonist removal have been implicated in autoreceptor function. Using G protein-coupled potassium (GIRK) channel activation in Xenopus oocytes as readout of receptor activity, we have investigated the voltage sensitivities and signaling kinetics of the hH(3)(445) and hH(3)(365) isoforms of the human histamine H₃ receptor, which functions as an inhibitory auto- and heteroreceptor in the nervous system. We have also investigated both the human and the mouse homologues of the related histamine H₄ receptor, which is expressed mainly on hematopoietic cells. We found that the hH(3)(445) receptor is the most sensitive to voltage, whereas the hH(3)(365) and H(4) receptors are less affected. We further observed a marked difference in response deactivation kinetics between the hH(3)(445) and hH(3)(365) isoforms, with the hH(3)(365) isoform being five to six-fold slower than the hH(3)(445) receptor. Finally, using synthetic agonists, we found evidence for agonist-specific voltage sensitivity at the hH₄ receptor. The differences in voltage sensitivities and deactivation kinetics between the hH(3)(445), hH(3)(365), and H₄ receptors might be relevant to their respective physiological roles.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. kristoffer.sahlholm@ki.se
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: D000595:Amino Acid Sequence; D000818:Animals; D055724:Electrophysiological Phenomena; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism*; D006801:Humans; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011968:Receptors, Histamine / Q000378:metabolism*; D018100:Receptors, Histamine H3 / Q000737:chemistry / Q000378:metabolism*; D000074040:Receptors, Histamine H4; D016415:Sequence Alignment; D014982:Xenopus laevis
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C418607:HRH4 protein, human; D020033:Protein Isoforms; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D000074040:Receptors, Histamine H4