5-HT7 receptors

Enterochromaffin cells are interspersed with mucosal cells mainly in the stomach and small intestine. In the blood, serotonin is present at high concentrations in platelets, which take up serotonin from the plasma by an active transport process. Serotonin is released on platelet activation. In the central nervous system, serotonin serves as a transmitter. The main serotonin-containing neurons are those clustered in form of the Raphe nuclei. Serotonin exerts its biological effects through the activation of specific receptors. Most of them are G-protein coupled receptors (GPCRs) and belong to the 5-HTr, 5-HT2-, 5-HT4-, 5-HTs-, 5-HT6-, 5-HT7-receptor subfamilies. The 5-HT3-receptor is a ligand-operated ion channel. 

HT4, 5-HTcAMP formation, yet they are regarded as distinct receptor classes because of their limited (<35%) overall sequence identities. This subdivision is arbitrary and may be subject to future modification. 

The 5-HTy receptor is part of the G-protein superfamily of receptors, which contains seven transmembrane regions, and its stimulation leads to an increase in cAMP production (Thomas Hagan, 2004). The 5-HT7 receptor is expressed in a number of telencephalic, diencephalic, mesencephalic, and rhombencephalic areas (Table 9.8). 

Serotonin shares with other neurotransmitters the ability to promote W and to suppress REMS. However, 5-HT participates in a variety of functions in addition to regulation of the behavioral state. Thus, as depicted in Tables 9.4-9.8, 5-HTia, 5-HTib, 5-HT2A/2C. 5-HT3, and 5-HT7 receptors are present in structures that... 

Recently, SB-269970 (l-[3-hydroxy-phenyl-sulphonyl]-2-[2-(4-methyl-l-piperidinyl)-ethyl] pyrrolidine) and SB-656104 (6-((R)-2- 2-[4-(4-chloro-phenoxy)-piperidin-l-yl]-ethyl pyrrolidine-l-sulphonyl)-lH-indole) have been reported to be potent 5-HT7 receptor antagonists (Hagan et al., 2000 Forbes et al., 2002). Selective 5-HT7 receptor agonists are not available at the present time. Systemic administration of SB-269970 or SB-656104 to rats at the beginning of the light period has been shown to reduce the total amount of REMS and to increase REMS latency. Values of W and SWS were not significantly modified (Hagan et al., 2000 Thomas et al., 2003). Hedlund et al. (2005) established that 5-HT7... 

In conclusion, based on neurochemical, electrophysiological, and neurophar-macological approaches, it is presently accepted that 5-HT functions to promote W and to inhibit REMS. Available evidence indicates that 5-HTiA, 5-HTiB, 5-HT2a. 5-HT2b, 5-HT2c, 5-HT3, and 5-HT7 receptors are involved in these effects. 

Hedlund, P. B., Huitron-Resendiz, S., Henriksen, S. J. 8r Sutcliffe, J. G. (2005). 5-HT7 receptor inhibition and inactivation induced antidepresssantlike behavior and sleep pattern. Biol. Psychiatry 58, 831-7. 

Monti, J. M. Jantos, H. (2006a). Effects of the 5-HT7 receptor antagonist SB-269970 microinjected into the dorsal raphe nucleus on REM sleep in the rat. Behav. 

Localization of 5-HT7 receptors in rat brain by immunocytochemistry, in situ hybridization, and agonist stimulated cFos expression. J. Chem. Neuroanat. 21, 63-73. 

Roberts, C., Thomas, D. R., Bate, S. T. Kew, J. N. C. (2004). GABAergic modulation of 5-HT7 receptor-mediated effects on 5-HT efflux in the guinea-pig dorsal raphe nucleus. Neuropharmacology 46, 935-41. 

Vanhoenacker, P., Haegeman, G. Leysen, J. E. (2000). 5-HT7 receptors current knowledge and future prospects. Trends Pharmacol. Sci. 21, 70-7. 

Unlike the other subtypes of receptor for 5-HT, the 5-HT3 receptor is a ligand-gated ion channel 245 The 5 n I 4 5-ht6 and 5-HT7 receptors are coupled to the stimulation of adenylyl cyclase 246... 

Three families of serotonin receptor, the 5-HT family, the 5-HT2 family and the family that includes the 5-HT4, 5-ht6 and 5-HT7 receptors represent the three major classes of 5-HT receptor that are G-protein-coupled receptors (Ch. 19). The 5-HT3 receptor is a ligand-gated ion channel and is a separate family. Although each serotonin receptor can be potently activated by 5-HT, differences insignal transduction mechanisms,neuroanatomical distribution and affinities for synthetic chemicals create opportunities for drug discovery and make each 5-HT receptor subtype a potential therapeutic target. 

The 5-HT4, 5-hts and 5-HT7 receptors are coupled to the stimulation of adenylyl cyclase. 5-HT4, 5-htg and 5-HT7 receptors preferentially couple to the stimulation of adenylyl cyclase, increasing cAMP formation, via the Gs family of G proteins (see Chs 19 and 21). These receptors, however, share only >35% overall sequence homology. For this reason, they are classified as distinct receptor groups or classes and not subtypes of a family. The grouping of these receptors together is considered to be somewhat arbitrary and may be modified in the future. A lower-case appellation is used for the 5-ht6 receptor because a physiological role for these receptors in intact tissue has not been found [28]. 

The 5-HT7 receptor is the most recently identified member of the family of G-protein-coupled 5-HT receptors. Although there is no selective agonist or antagonist currently available for the 5-HT7 receptor, the distinct pharmacological profile of 5-HT7 receptor sites has been used to delineate the function and distribution of this... 

A role for the 5-HT7 receptor in the regulation of circadian rhythms has been implicated. As discussed above, 5-HT has been known for some time to induce phase shifts in behavioral circadian rhythms and modulate neuronal activity in the suprachiasmatic nucleus, the likely site of the mammalian circadian clock. The pharmacological characteristics of the effect of 5-HT on circadian rhythms are consistent with 5-HT7 receptor. Moreover, mRNA for the 5-HT7 receptor is found in the suprachiasmatic nucleus. There is also increasing evidence that the 5-HT7 receptor may play a role in psychiatric disorders. The regional distribution of 5-HT7 receptors in brain includes limbic areas and cortex. Atypical antipsychotics, such as clozapine and risperidone, and some antidepressants display high affinity for this receptor. In the periphery, 5-HT7 receptors havebeenshown to mediate relaxation of vascular smooth muscle. 

Alternative mRNA splicing has been reported to generate four 5-HT7 receptor iso forms. However, these iso forms have not been shown to differ in their respective pharmacology, signal transduction or tissue distribution. 

Figure 6.7. Distribution of 5-HT5 and 5-HT7 receptors. Unlike the widely distributed S-HT and 5-HT2 receptors, the 5-HT5 receptors are primarily located in the hippocampus and the 5-HT7 receptors restricted to the thalamus.

Hedlund PB, Sutcliffe JG. Functional, molecular and pharmacological advances in 5-HT7 receptor research. Trends Pharmacol Sci 2004 25 481-6. 

Hedlund PB, Danielson PE, Thomas EA, Slanina K, Carson MJ, SutcUffe JG (2003) No hypothermic response to serotonin in 5-HT7 receptor knockout mice. Proc Natl Acad SciUS A 100 1375-1380... 

---