Connelly, WM and Shenton, FC and Lethbridge, N and Leurs, R and Waldvogel, HJ and Faull, RLM and Lees, G and Chazot, PL, The histamine H4 receptor is functionally expressed on neurons in the mammalian CNS, British Journal of Pharmacology, 157, (1) pp. 55-63. ISSN 0007-1188 (2009) [Refereed Article]
© 2009 The Authors
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 (20 mmol·L-1 ) suggesting that H4 receptors did not act as hetero-receptors on thalamocortical glutamatergic terminals.
Conclusions and implications: This is the first demonstration that histamine H4 receptors are functionally expressed on neurons, which has major implications for the therapeutic potential of these receptors in neurology and psychiatry.
|Item Type:||Refereed Article|
|Research Division:||Medical and Health Sciences|
|Research Field:||Cellular Nervous System|
|Objective Group:||Clinical Health (Organs, Diseases and Abnormal Conditions)|
|Objective Field:||Nervous System and Disorders|
|UTAS Author:||Connelly, WM (Dr William Connelly)|
|Web of Science® Times Cited:||133|
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