The histamine H₄ receptor is functionally expressed on neurons in the mammalian CNS

Abstract

Background and purpose:The histamine H4 receptor is the most recently identified of the G protein-coupled histamine receptor family and binds several neuroactive drugs, including amitriptyline and clozapine. So far, H4 receptors have been found only on haematopoietic cells, highlighting its importance in inflammatory conditions. Here we investigated the possibility that H4 receptors may be expressed in both the human and mouse CNS. Methods: Immunological and pharmacological studies were performed using a novel anti-H4 receptor antibody in both human and mouse brains, and electrophysiological techniques in the mouse brain respectively. Pharmacological tools, selective for the H4 receptor and patch clamp electrophysiology, were utilized to confirm functional properties of the H4 receptor in layer IV of the mouse somatosensory cortex. Results: Histamine H4 receptors were prominently expressed in distinct deep laminae, particularly layer VI, in the human cortex, and mouse thalamus, hippocampal CA4 stratum lucidum and layer IV of the cerebral cortex. In layer IV of the mouse somatosensory cortex, the H4 receptor agonist 4-methyl histamine (20 mmol·L -1 ) directly hyperpolarized neurons, an effect that was blocked by the selective H4 receptor antagonist JNJ 10191584, and promoted outwardly rectifying currents in these cells. Monosynaptic thalamocortical CNQX-sensitive excitatory postsynaptic potentials were not altered by 4-methyl histamine

Overexpression of histamine H4 receptors in the kidney of diabetic rat

“…Conventional immunohistochemical procedures were employed as described previously [30,31] AQP3, -NKCC1, -TNAP and -THP (4 µg/ml) at 4°C, followed by a three-layer streptavidin-biotin-peroxidase complex staining method (Vectastain ABC Elite kit and 3',3-diaminobenzadine tetrahydrochloride, DAB; Vector Laboratories, Inc.). Tissue was also screened in the absence of primary antibody.…”

Pleiotropic effect of histamine H4 receptor modulation in the central nervous system

“…H4R expression has been reported in peripheral nerves and in the neurons of the submucous plexus (Nakaya et al, 2004;Breunig et al, 2007). More recently it has been observed the presence of H4R receptors in numerous areas of the central nervous system (CNS), such as hippocampus, thalamus, amygdala, cortex, striatum and spinal cord (Strakhova et al, 2009;Connelly et al, 2009). Electrophysiological studies showed that H4R directly hyperpolarized cortical neurons (Connelly et al, 2009).…”

“…More recently it has been observed the presence of H4R receptors in numerous areas of the central nervous system (CNS), such as hippocampus, thalamus, amygdala, cortex, striatum and spinal cord (Strakhova et al, 2009;Connelly et al, 2009). Electrophysiological studies showed that H4R directly hyperpolarized cortical neurons (Connelly et al, 2009). More recent studies on the potential roles for H4R in the human brain from its predicted functional interactions in the human proteome suggested the participation of H4R in circadian cycle modulation, neuronal firing inhibition and, in cooperation with H3R, in thyroid function and appetite coordination (Moya-Garcia et al, 2011).…”

The histamine H3-receptor inverse agonist Pitolisant improves fear memory in mice

“…Histamine is synthesized from l-histidine by the enzyme histidine decarboxylase (HDC) and its effects are mediated by four histamine receptors in the brain: the histamine H 1 , H 2 , H 3 and H 4 receptors (H 1 R, H 2 R, H 3 R and H 4 R). H 1 R and H 2 R are mainly postsynaptic excitatory receptors whereas H 3 R and H 4 R are inhibitory receptors coupled to G i/o proteins [7,8]. H 3 R were originally described as presynaptic autoreceptors located on histaminergic axons and their activation inhibits the release and synthesis of histamine [9].…”