Functional, endogenously expressed 5‐hydroxytryptamine 5‐ht<sub>7</sub> receptors in human vascular smooth muscle cells

Schoeffter, Philippe; Ullmer, Christoph; Bobirnac, Ionel; Gabbiani, Giulio; Lübbert, Hermann

doi:10.1111/j.1476-5381.1996.tb16687.x

Cited by 49 publications

(43 citation statements)

References 6 publications

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“…The brain, heart, small intestine and testis contained the highest levels of expression. Due to the presence of h5-HT 7(a) mRNA in the vasculature (Bard et al 1993;Jasper et al 1997;Schoeffter et al 1996;Ullmer et al 1995), it is tempting to speculate that the ubiquitous expression of h5-HT 7(a) mRNA may result in part from mRNA derived from the vasculature of the tissue. Thus far, the h5-HT 7(b) splice variant is reportedly expressed in multiple brain regions, aorta, small intestine, stomach and spleen (Heidmann et al 1997;Jasper et al 1997).…”

Section: Discussionmentioning

confidence: 97%

“…Diverse physiological roles of 5-HT 7 receptors have been implicated in multiple organ systems, such as the cardiovascular system (De Vries et al 1999;Schoeffter et al 1996;Terron and Falcon-Neri 1999;Ullmer et al 1995;Villalon et al 1997), CNS (Cohen et al 1999;Eglen et al 1997;Héry et al 1997;Saxena et al 1998) and digestive tract (Carter et al 1995). Despite the increased understanding of the putative physiological roles of the 5-HT 7 receptor (see Eglen et al 1997 for review), little is known about which splice variants are mediating these effects.…”

Section: Introductionmentioning

confidence: 98%

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The cloned human 5-HT 7 receptor splice variants: a comparative characterization of their pharmacology, function and distribution

Krobert

Bach

Syversveen

et al. 2001

Naunyn-Schmiedeberg's Archives of Pharmacology

140

156

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Serotonin (5-hydroxytryptamine, 5-HT) receptor pre-mRNA is alternatively spliced in human tissue to produce three splice variants, h5-HT7(a), h5-HT7(b) and h5-HT7(d), which differ only in their carboxyl terminal tails. Using membranes from transiently and stably transfected HEK293 cells expressing the three recombinant h5-HT7 splice variants we compared their pharmacological profiles and ability to activate adenylyl cyclase. Using PCR on cDNA derived from various human tissues, the 5-HT7(a) and 5-HT7(b) splice variants were detected in every tissue examined. The h5-HT7(d) splice variant was detected in 13 of 16 tissues examined, with predominant expression in the heart, small intestine, colon, ovary and testis. All three h5-HT7 splice variants displayed high affinity binding for [3H]5-HT (pKd=8.8-8.9) in the presence and absence of 100 microM GTP and had similar binding affinities for all 17 ligands evaluated. In HEK293 cells expressing similar, high levels of receptor (approximately 10,000 fmol/mg protein), 5-CT (5-carboxamidotryptamine), 5-MeOT (5-methoxytryptamine) and 5-HT were full agonists while 8-OH-DPAT ((2R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin) was a partial agonist with relative efficacy of approximately 0.8. Even at this high receptor level, EC50 values for stimulation of adenylyl cyclase were 10- to 50-fold higher than the Kd values, indicating a lack of spare receptors. No significant differences in coupling to adenylyl cyclase were observed between the three splice variants over a wide range of receptor expression levels. For antagonists, binding affinities determined by displacement of [3H]5-HT binding and by competitive inhibition of 5-HT-stimulated adenylyl cyclase activity were essentially identical amongst the splice variants. These studies indicate that the three human splice variants are pharmacologically indistinguishable and that modifications of the carboxyl tail do not influence coupling to adenylyl cyclase.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 98%

The cloned human 5-HT 7 receptor splice variants: a comparative characterization of their pharmacology, function and distribution

Krobert

Bach

Syversveen

et al. 2001

Naunyn-Schmiedeberg's Archives of Pharmacology

140

156

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“…The variants encode receptors that have slightly different lengths of the C termini, but with no detectable difference in tissue distributions or functional couplings (13). The 5-HT 7 receptor has also been detected in the periphery, where it is found primarily in smooth muscle cells of blood vessels (2,14), but also in the gastrointestinal tract (2).…”

mentioning

confidence: 99%

“…Early evidence supported by the pharmacological profile suggested that the 5-HT 7 receptor mediates the 5-HT-induced phase resetting of the circadian clock within the suprachiasmatic nucleus of the hypothalamus (1). The ability of 5-HT 7 receptors to mediate smooth muscle relaxation (14,20) has led to the suggestion that ligands may have therapeutic value in migraine (21). The 5-HT 7 receptor has also been implicated in endocrine regulation and neuropsychiatric disorders (22).…”

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confidence: 99%

No hypothermic response to serotonin in 5-HT ₇ receptor knockout mice

Hedlund

Danielson

Thomas

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

167

125

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With data from recently available selective antagonists for the 5-HT7 receptor, it has been hypothesized that 5-hydroxytryptamine (5-HT)-induced hypothermia is mediated by the 5-HT7 receptor, an effect previously attributed to other receptor subtypes. It has been established that the biologically active lipid oleamide allosterically interacts with the 5-HT7 receptor to regulate its transmission. The most well characterized effects of oleamide administration are induction of sleep and hypothermia. Here, we demonstrate, by using mice lacking the 5-HT7 receptor, that 5-HTinduced hypothermia is mediated by the 5-HT7 receptor. Both 5-HT and 5-carboxamidotryptamine, a 5-HT1 and 5-HT7 receptor agonist, in physiological doses fail to induce hypothermia in 5-HT7 knockout mice. In contrast, oleamide was equally effective in inducing hypothermia in mice lacking the 5-HT7 receptors as in wild-type mice. When administered together, 5-HT and oleamide showed additive or greater than additive effects in reducing body temperature. Taken together, the results show that 5-HT-induced hypothermia is mediated by the 5-HT7 receptor, and that oleamide may act through an independent mechanism as well as at an allosteric 5-HT7 receptor site to regulate body temperature. The 5-HT 7 receptor is one of the most recently described members of the large family of serotonin [5-hydroxytryptamine (5-HT)] receptors (1, 2). cDNA clones of the mRNAs encoding this receptor have been isolated from several different species, including mouse, rat, guinea pig, and human. In all species, the 5-HT 7 receptor shows a consistent mRNA distribution pattern within the brain (1, 3, 4) and ligand binding profile (5-8). The 5-HT 7 receptor is mainly localized to the hypothalamus, hippocampus, and frontal cortex.Functionally, the 5-HT 7 receptor has been shown to stimulate cAMP formation (1, 2, 6, 7). This stimulation has been linked to the activation of a calmodulin-regulated adenylyl cyclase (9). The existence of several splice variants of the 5-HT 7 receptor mRNA has been clearly demonstrated (10-12). The variants encode receptors that have slightly different lengths of the C termini, but with no detectable difference in tissue distributions or functional couplings (13). The 5-HT 7 receptor has also been detected in the periphery, where it is found primarily in smooth muscle cells of blood vessels (2, 14), but also in the gastrointestinal tract (2).Early studies established a pharmacological profile that distinguished 5-HT 7 receptors from other 5-HT receptors. The 5-HT 7 receptor shows a high affinity for 5-HT, 5-carboxamidotryptamine (5-CT), and methiothepin, relatively high affinity for 8-hydroxy-[N-n-dipropyl-N-(3Ј-iodo-2Јpropenyl)amino]tetralin (8-OH-DPAT) and ritanserin, and low affinity for pindolol and buspirone (1, 15). Recently, more selective antagonists have been described (16)(17)(18)(19), developments that will facilitate the characterization of the 5-HT 7 receptor.The 5-HT 7 receptor has been linked to a number of physiological and pathophysiologi...

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“…In addition, the expression of the 5-HT 7 receptor in the suprachiasmatic nucleus (SCN) and the ability of serotonin and cAMP to advance the mammalian circadian rhythm indicates that 5-HT 7 plays an important role in circadian physiology (10,14,15). 5-HT 7 receptors are also expressed in glial cells (16,17) and at lower levels in peripheral tissues including the spleen, intestine, and vascular smooth muscle (7)(8)(9)18).…”

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confidence: 99%

Stimulation of Type 1 and Type 8 Ca2+/Calmodulin-sensitive Adenylyl Cyclases by the Gs-coupled 5-Hydroxytryptamine Subtype 5-HT7AReceptor

Baker

Nielsen

Impey

et al. 1998

Journal of Biological Chemistry

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The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) plays an important regulatory role in developing and adult nervous systems. With the exception of the 5-HT 3 receptor, all of the cloned serotonin receptors belong to the G protein-coupled receptor superfamily. Subtypes 5-HT 6 and 5-HT 7 couple to stimulation of adenylyl cyclases through G s and display high affinities for antipsychotic and antidepressant drugs. In the brain, mRNA for 5-HT 6 is found at high levels in the hippocampus, striatum, and nucleus accumbens. 5-HT 7 mRNA is most abundant in the hippocampus, neocortex, and hypothalamus. To better understand how serotonin might control cAMP levels in the brain, we coexpressed 5-HT 6 or 5-HT 7A receptors with specific isoforms of adenylyl cyclase in HEK 293 cells. The 5-HT 6 receptor functioned as a typical G s -coupled receptor in that it stimulated AC5, a G s -sensitive adenylyl cyclase, but not AC1 or AC8, calmodulin (CaM)-stimulated adenylyl cyclases that are not activated by G s -coupled receptors in vivo. Surprisingly, serotonin activation of 5-HT 7A stimulated AC1 and AC8 by increasing intracellular Ca 2؉ . 5-HT also increased intracellular Ca 2؉ in primary neuron cultures. These data define a novel mechanism for the regulation of intracellular cAMP by serotonin. Serotonin (5-hydroxytryptamine, 5-HT)1 is a ubiquitous neurotransmitter that elicits a variety of physiological effects peripherally and centrally (1-3). A growing family of plasma membrane receptors bind 5-HT and mediate its cellular effects (4). All of the 5-HT receptors except 5-HT 3 belong to the superfamily of G protein-coupled receptors. The recently cloned 5-HT 6 (5, 6) and 5-HT 7 (7-10) receptors activate adenylyl cyclase(s) through the heterotrimeric G protein G s , and expression of these receptors in cultured cells couples serotonin to increases in cAMP (6,8). 5-HT 6 and 5-HT 7 display high affinities for antipsychotic and antidepressant drugs including clozapine, amoxapine, and amitryptiline (5-8), suggesting a role for these receptors in affective function. In the brain, the 5-HT 6 receptor is most highly expressed in the hippocampus, nucleus accumbens, striatum, and limbic regions, and the 5-HT 7 receptor is found in the hypothalamus, hippocampus, and cortex. The distribution of these receptors in brain is consistent with the hypothesis that they play a role in mood and affect (8,(11)(12)(13). In addition, the expression of the 5-HT 7 receptor in the suprachiasmatic nucleus (SCN) and the ability of serotonin and cAMP to advance the mammalian circadian rhythm indicates that 5-HT 7 plays an important role in circadian physiology (10, 14, 15). 5-HT 7 receptors are also expressed in glial cells (16,17) and at lower levels in peripheral tissues including the spleen, intestine, and vascular smooth muscle (7-9, 18).Many psychotherapeutic agents modulate the cAMP signaling pathway (19) and perturbation of this signal transduction system may contribute to some affective disorders. To date, nine distinct cDNA clones for mammalian...

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Functional, endogenously expressed 5‐hydroxytryptamine 5‐ht₇ receptors in human vascular smooth muscle cells

Cited by 49 publications

References 6 publications

The cloned human 5-HT 7 receptor splice variants: a comparative characterization of their pharmacology, function and distribution

The cloned human 5-HT 7 receptor splice variants: a comparative characterization of their pharmacology, function and distribution

No hypothermic response to serotonin in 5-HT ₇ receptor knockout mice

Stimulation of Type 1 and Type 8 Ca2+/Calmodulin-sensitive Adenylyl Cyclases by the Gs-coupled 5-Hydroxytryptamine Subtype 5-HT7AReceptor

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Functional, endogenously expressed 5‐hydroxytryptamine 5‐ht7 receptors in human vascular smooth muscle cells

Cited by 49 publications

References 6 publications

The cloned human 5-HT 7 receptor splice variants: a comparative characterization of their pharmacology, function and distribution

The cloned human 5-HT 7 receptor splice variants: a comparative characterization of their pharmacology, function and distribution

No hypothermic response to serotonin in 5-HT 7 receptor knockout mice

Stimulation of Type 1 and Type 8 Ca2+/Calmodulin-sensitive Adenylyl Cyclases by the Gs-coupled 5-Hydroxytryptamine Subtype 5-HT7AReceptor

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Functional, endogenously expressed 5‐hydroxytryptamine 5‐ht₇ receptors in human vascular smooth muscle cells

No hypothermic response to serotonin in 5-HT ₇ receptor knockout mice