Review
Constitutive activity of the histamine H3 receptor

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Constitutive activity has been mainly recorded for numerous overexpressed and/or mutated receptors. The histamine H3 receptor (H3R) is a target of choice to study the physiological relevance of this process. In rodent brain, postsynaptic H3Rs show high constitutive activity, and presynaptic H3 autoreceptors that show constitutive activity have a predominant role in inhibiting the activity of histamine neurons. H3R inverse agonists abrogate this constitutive brake and enhance histamine release in vivo. Some of these inverse agonists have entered clinical trials for the treatment of cognitive and food intake disorders. Studies performed in vitro and in vivo with proxyfan show that this H3R ligand is a ‘protean agonist’ – that is, a ligand with a spectrum of activity ranging from full agonism to full inverse agonism depending on the level of H3R constitutive activity. Consistent with its physiological and therapeutic relevance, the constitutive activity of H3R thus has a major function in the brain and regulates the activity of H3R-targeted drugs.

Introduction

Current models of G-protein-coupled receptor (GPCR) activation assume that receptors exist in equilibrium between inactive and active conformations. Active conformations are promoted by agonists but also exist in the absence of an agonist (see Glossary), thereby leading to constitutive (or spontaneous) receptor activity. The level of constitutive activity depends on both the number of spontaneously active conformations and the coupling efficiency of these conformations to G proteins. It therefore depends not only on the receptor, but also on the response. Inverse agonists abrogate constitutive activity by promoting inactive conformations. Their maximal effect is correlated to the level of constitutive activity. This direct relationship explains why constitutive activity was first observed for recombinant receptors that were overexpressed and/or mutated 1, 2. Although indirect indications also suggested that constitutive activity of native GPCRs occurs in tissues [3], the physiological relevance of the process was initially debated because of the potential contribution of endogenous agonists to the activity observed.

After the discovery of constitutive activity, the concept of ‘protean agonism’ (named after Proteus, a Greek god who could change shape at will) was introduced on theoretical grounds [4]. The rationale was that the reversal from agonism to inverse agonism occurred when the conformation induced by an agonist showed an efficacy lower than that of the constitutively active conformation of the receptor in the same system. It was therefore predicted that a protean agonist could act as either an agonist or an inverse agonist at the same GPCR, depending on the level of constitutive activity. Protean agonism has been subsequently reported in cell lines expressing various GPCRs such as α2A-adrenoceptors 5, 6, β2-adrenoceptors [7], secretin receptors [8], lysophosphatidic acid receptor-1 [9] and cannabinoid CB2 receptors [10]. Until recently, however, the process remained to be observed under physiological conditions.

The histamine H3 receptor (H3R) was identified in 1983 as an autoreceptor located on histamine-containing nerve endings that controls histamine synthesis and release in the brain 11, 12, 13. The design of selective ligands showed that H3Rs provide the main mechanism for the physiological regulation of histamine neuron activity 13, 14. These selective ligands have been subsequently used in hundreds of studies to modify the activity of histamine-containing neurons, and thereby to disclose their functions. Such studies have shown that H3Rs are involved in the histamine-mediated regulation of important processes such as arousal, cognitive processes and food intake 14, 15, 16.

Not all cerebral H3Rs are autoreceptors. Presynaptic H3 heteroreceptors inhibit the release of various neurotransmitters 14, 17, and postsynaptic H3Rs are located on the perikarya of many neuronal populations [18]. The physiological role of these H3Rs remains, however, unknown.

The H3R was cloned in humans in 1999 [19]. This cloning was an important step for molecular studies and drug design. Although thousands of H3R ligands, some aimed at clinical use, had been optimized in rat, the pharmacological profiles of the recombinant human and rat H3R receptors are different [20]. Thus, the possibility of screening ligands at the human H3R represented a major advance in the field. Molecular studies confirmed that the H3R is coupled to Gi/o proteins. Its activation enhances binding of the GTP analog [35S]GTPγS to cell or brain membranes 21, 22, 23. Activation of recombinant rat and human H3R inhibits cAMP accumulation, enhances arachidonic acid release, and activates the ERK kinase signaling pathway 14, 24.

In different species including human, molecular studies have shown that functional isoforms are generated by deletion of a pseudo-intron that varies in length and is located in the third intracellular loop of the H3R [25]. The distribution and pharmacology of these isoforms are different. Their respective functions in the brain remain unknown, but they might generate heterogeneity of the cerebral H3R [14].

As we review here, the H3R has become a GPCR of choice for studies of constitutive activity and protean agonism. Consistent with the physiological relevance of the process, H3Rs present in the brain show high constitutive activity. Moreover, the high constitutive activity of H3Rs has been used to investigate protean agonism experimentally.

Section snippets

Constitutive activity of H3Rs

Constitutive activity of the rat and human H3R was first recognized through the signaling changes generated by their expression in cells. As compared with wild-type cells, the expression of H3Rs in cell lines enhances arachidonic acid release and [35S]GTPγS binding, and reduces cAMP accumulation 22, 23, 26 (Box 1). As expected, the level of constitutive activity of the H3R at a given density varies with the cell line and signaling pathway [27]. The [35S]GTPγS binding generated by expression of

Protean agonism at H3Rs

The high constitutive activity of H3Rs made possible the experimental demonstration of ‘protean agonism’ in vitro and in vivo. Although it has been classified as a neutral antagonist [14], proxyfan acts in fact as a protean agonist at H3Rs [27]. When proxyfan is compared against histamine (agonist) and ciproxifan (inverse agonist) in various H3R-mediated responses, it shows a spectrum of activity ranging from full agonism to full inverse agonism, depending on the level of H3R constitutive

Therapeutic potential of H3R inverse agonists

The best-studied effect of H3R inverse agonists is to enhance the activity of histamine neurons; thus, the therapeutic interest in these inverse agonists is largely based on the waking, pro-cognitive and anti-obesity roles of brain histamine neurons [14]. This interest has been dedicated for many years to H3R antagonists, most of which have now been reclassified as inverse agonists.

Despite its complexity, the H3R has become an attractive drug target in the central nervous system. Numerous

Concluding remarks

In summary, consistent with the physiological relevance of the process, H3R constitutive activity has a major regulatory role in the brain. It also has a considerable role in regulating the activity of H3R ligands, as shown by the experimental evidence for H3R protean agonism. Protean agonists such as proxyfan are powerful tools with which to investigate active receptor conformations, and they support a multistate model of GPCR activation. H3R inverse agonists targeting important diseases such

Glossary

Agonist
a drug that stabilizes the receptor in an active conformation (state). Active conformations couple to G proteins to initiate a response.
Anorectic inverse agonist
an inverse agonist that decreases food intake after its administration.
Autoreceptor
a receptor through which a neurotransmitter regulates its own release from a neuron. An autoreceptor is a presynaptic receptor located on nerve endings that usually inhibits neurotransmitter release.
Constitutive activity
the spontaneous activity

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