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Constitutive activity of the histamine H3 receptor

2007; Elsevier BV; Volume: 28; Issue: 7 Linguagem: Inglês

10.1016/j.tips.2007.05.002

1873-3735

Jean-Michel Arrang, Séverine Morisset‐Lopez, Florence Gbahou,

Receptor Mechanisms and Signaling

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. 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. a drug that stabilizes the receptor in an active conformation (state). Active conformations couple to G proteins to initiate a response. an inverse agonist that decreases food intake after its administration. 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. the spontaneous activity shown by a receptor in the absence of any agonist. Constitutive activity is generated by constitutively active conformations that are pre-coupled to G proteins. a presynaptic receptor activated by an agonist other than the neuron's own neurotransmitter and that enhances or inhibits neurotransmitter release. a drug that stabilizes the receptor in an inactive conformation. It decreases spontaneous coupling of the receptor to G proteins, thereby suppressing constitutive activity. In the absence of constitutive activity, inverse agonists behave as antagonists. a compound that has no apparent effect in a system with constitutive activity, but blocks the effects of both agonists and inverse agonists. whereas a full agonist produces the maximal response of a given system, a partial agonist produces a maximal response that is lower than that obtained with a full agonist in the same system. whereas a full inverse agonist fully abrogates constitutive activity, a partial inverse agonist only partially reduces constitutive activity in the same system. a drug that can produce different responses, ranging from full agonism to full inverse agonism, depending on the level of constitutive activity in the system. a brain preparation enriched in functional nerve terminals. Synaptosomes are commonly used to study presynaptic mechanisms because they contain the molecular machinery necessary for the uptake, storage and release of neurotransmitters.