Voltage sensitivities and deactivation kinetics of histamine H 3 and H 4 receptors

摘要

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 H 3 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 H 4 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 hH 4 receptor. The differences in voltage sensitivities and deactivation kinetics between the hH 3 445, hH 3 365, and H 4 receptors might be relevant to their respective physiological roles.