The Histamine H₃Receptor: Structure, Pharmacology, and Function

Abstract

Among the four G protein-coupled receptors (H-H) identified as mediators of the biologic effects of histamine, the H receptor (HR) is distinguished for its almost exclusive expression in the nervous system and the large variety of isoforms generated by alternative splicing of the corresponding mRNA. Additionally, it exhibits dual functionality as autoreceptor and heteroreceptor, and this enables HRs to modulate the histaminergic and other neurotransmitter systems. The cloning of the HR cDNA in 1999 by Lovenberg et al. allowed for detailed studies of its molecular aspects. In this work, we review the characteristics of the HR, namely, its structure, constitutive activity, isoforms, signal transduction pathways, regional differences in expression and localization, selective agonists, antagonists and inverse agonists, dimerization with other neurotransmitter receptors, and the main presynaptic and postsynaptic effects resulting from its activation. The HR has attracted interest as a potential drug target for the treatment of several important neurologic and psychiatric disorders, such as Alzheimer and Parkinson diseases, Gilles de la Tourette syndrome, and addiction.

Histamine, histamine receptors, and anti-histamines in the context of allergic responses

“…The full length human H 1 , H 2 , H 3 , and H 4 receptors are composed of 487, 359, 445, and 390 amino acids, respectively (Simons 2004). H 4 receptor has 40% homology with the H 3 receptor, and was identified based on differences in tissue distribution and binding affinity (Nakamura et al 2000). Liu et al (2001) identified 35% homology between the H 4 receptor and the H 3 receptor (Table 1).…”

“…Acting through the presynaptic H 3 receptor, histamine regulates its own release (negative feedback) as well as the release of other neurotransmitters such as noradrenaline, dopamine, serotonin, acetylcholine, and gammaamino-butyric acid. In the lower airways, H 3 receptors are located on postganglionic cholinergic nerves and counteracts bronchoconstriction, through stimulation of phospholipase A2 and subsequent enhanced release of endothelium-derived relaxing factor in guinea pigs (Barnes 1991;Burgaud and Oudart 1993;Nieto-Alamilla et al 2016). In the upper airways, histamine may play a role in nasal congestion through its activity at H 3 receptors.…”

In silico and in vitro studies of two non‐imidazole multiple targeting agents at histamine H3 receptors and cholinesterase enzymes

“…These receptors are mainly located in different areas of CNS regulating the release of histamine and other neurotransmitter such as acetylcholine and dopamine through a negative feedback mechanism. The H 3 R belongs to the superfamily of G protein‐coupled receptors and is coupled to the G i/o class of G proteins, leading to inhibition of the adenylyl cyclase with the subsequent decrease in the level of cAMP, among other actions (Nieto‐Alamilla, Marquez‐Gomez, Garcia‐Galvez, Morales‐Figueroa, & Arias‐Montano, ). There are lines of evidence indicating that H 3 R blockade enhances acetylcholine release, thereby leading to improved cognitive and behavioral symptoms (Brioni, Esbenshade, Garrison, Bitner, & Cowart, ; Medhurst et al, ; Raddatz, Tao, & Hudkins, ; Sadek, Saad, Sadeq, Jalal, & Stark, ).…”

Pharmacological andSARanalysis of theLINS01 compounds at the human histamine H1, H2, and H3receptors

“…H 3 R antagonists have been investigated as potential treatments for several CNS disorders, including sleep disorders, schizophrenia, epilepsy, attention deficit, hyperactivity disorder, and even obesity. There is also potential for H 3 R antagonists to have effects in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's chorea . Recently, a H 3 R antagonist (pitolisant) has been approved for the maintenance of wakefulness in patients with narcolepsy .…”