H3-autoreceptor

Figure 22.7 Histamine influences on sleep and arousal. The activity of histamine-releasing neurons increases with arousal and diminishes during sleep. Both Hi antagonists and agonists of H3-autoreceptors depress release of histamine and reduce arousal (see text for details)...

The activity of histaminergic neurons is regulated by H3 autoreceptors and by other transmitter receptors 255... 

Unlike catecholamines and indoleamines, histamine itself is not a direct inhibitor of its biosynthetic enzyme, but it exerts feedback control through the H3 autoreceptor. Perhaps the most powerful tool in the study of the histamine system is S-a-fluoromethylhistidine, a highly selective and potent suicide inhibitor of HDC [22]. This compound has been used successfully to study many of the functions of histamine in brain. 

Gomez-Ramirez, J., Ortiz, J. and Blanco, I. Presynaptic H3 autoreceptors modulate histamine synthesis through cAMP pathway. Mol. Pharmacol. 61 239-245, 2002. 

The term "H3 receptor" has been coined by Arrang et al.1 H3 receptors are located on paracrine cells and on neurones activation of H3 receptors usually causes inhibition of the release of the respective mediator or neurotransmitter. The receptor characterized by Arrang et al.1 is an example of an autoreceptor, i.e. of a receptor via which the transmitter released from a given neurone influences its own release. H3 receptor-mediated inhibition of the release of transmitters other than histamine has also been described such receptors are known as heteroreceptors. The present review will focus on H3 heteroreceptors in the central nervous system (CNS) in separate chapters of this book, H3 autoreceptors, H3 heteroreceptors in the neuroendocrine system as well as H3 receptor-mediated modulation of transmitter release in vivo will be considered. A separate article will also deal with H3 heteroreceptors in peripheral tissues although an example of an H3 receptor in the retina will be covered in our chapter, due to the close relationship between CNS and retina2. 

Presynaptic H3 receptors also are uniform in their signal transduction. They couple to Gi/o proteins and decrease the depolarization-induced release of neurotransmitters by inhibiting multiple calcium channels (e.g., Arrang et al. 1985 Schlicker et al. 1994 Endou et al. 1994 Brown and Haas 1999 see Stark et al. 2004). For comparison, the signal transduction of soma-dendritic H3 autoreceptors in histamin-ergic neurons also involves a pertussis toxin-sensitive G-protein with subsequent inhibition of N- and P-type Ca2+ channels (Takeshita et al. 1998). The few exceptions to this signal transduction pathway are discussed in the corresponding subsections below (see Sections 3.1, 3.3, and 3.9). 

Like presynaptic dopamine autoreceptors, presynaptic histamine autoreceptors are activated by the released endogenous transmitter to inhibit further histamine release, as shown by the increase in histamine release caused by antagonists at H3 receptors a definite piece of physiology. Evidence has been presented recently that cardiac postganglionic sympathetic neurons of the guinea pig synthesize and release histamine as a co-transmitter (Li et al. 2003 2006). These noradrenaline-histamine neurons possess H3 autoreceptors which, when activated, depress the release of both noradrenaline and histamine - unlike the D2-like autoreceptors of dopamine-neurotensin neurons which modulate the release of the two cotransmitters in opposite direction (see Section 2.2). It would be of interest to see whether, conversely, activation of ot2-autoreceptors inhibits the release of histamine in the guinea pig heart. 

Apart from exocytosis, presynaptic H3 autoreceptors also inhibit the synthesis of histamine at the level of nerve endings, at least in part through pathways distinct from those leading to the inhibition of release. One pathway is inhibition of adenylyl cyclase (Gomez-Ramirez et al. 2002 Moreno-Delgado et al. 2006) activation of cAMP-dependent protein kinase A by cAMP stimulates histamine synthesis through phosphorylation of histidine decarboxylase, and this stimulation is diminished when adenylyl cyclase activity decreases following activation of H3 autoreceptors and Gi/o proteins. 

Wherever histamine neurons are involved in pathophysiology, their H3 autoreceptors surely are involved as well. For example, histamine release in the prefrontal cortex is increased during handling stress, and this increase is potentiated when H3 autoreceptors are blocked (Westerink et al. 2002). 

Gomez-Ramirez J, Ortiz J, Blanco I (2002) Presynaptic H3 autoreceptors modulate histamine synthesis through cAMP pathway. Mol Pharmacol 61 239-45 Goncalves J, Bultmann R, Driessen B (1996) Opposite modulation of cotransmitter release in guinea pig vas deferens increase of noradrenaline and decrease of ATP release by activation of prejunctional beta-adrenoceptors. Naunyn-Schmiedeberg s Arch Pharmacol 353 184-92 Gonzalez-Islas C, Hablitz J (2001) Dopamine inhibition of evoked IPSCs in rat prefrontal cortex. J Neurophysiol 86 2911-18... 

Mooney RD, Shi MY, Rhoades RW (1994) Modulation of retinotectal transmission by presynaptic 5-HTib receptors in the superior colliculus of the adult hamster. J Neurophysiol 72 3-13 Moreno-Delgado D, Torrent A, Gomez-Ramirez J, de Esch I, Blanco I, Ortiz J (2006) Constitutive activity of H3 autoreceptors modulates histamine synthesis in rat brain through the cAMP/PKA pathway. Neuropharmacology 51 517-23... 

Westerink BH, Cremers TI, De Vries JB, Liefers H, Tran N, De Boer P (2002) Evidence for activation of histamine H3 autoreceptors during handling stress in the prefrontal cortex of the rat. Synapse 43 238-43... 

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