Disease relevance of Htr4

• These results provide the first example of a genetic deficit that disrupts the ability of stress to reduce feeding and body weight and suggest that 5-HT4 receptors may be involved in stress-induced anorexia and seizure susceptibility [1].
• Attenuated response to stress and novelty and hypersensitivity to seizures in 5-HT4 receptor knock-out mice [1].
• Several rodent studies have also suggested that intact 5-HT systems are important determinants of sensitivity and/or tolerance to ethanol-induced ataxia and hypothermia [2].
• Neuropsychiatric disorders such as anxiety, depression, migraine, vasospasm and epilepsy may involve different subtypes of the 5-hydroxytryptamine (5-HT) receptor [3].
• It has been suggested that reserpine blocks expression of delayed hypersensitivity (DH) by depleting tissue mast cells of serotonin (5-HT), thereby preventing a T cell-dependent release of mast cell 5-HT necessary to localize and to amplify the DH response [4].

Psychiatry related information on Htr4

• Based on these findings, it could be inferred that the increase of brain Allo content elicited by fluoxetine and norfluoxetine, rather than the inhibition selective of 5-HT reuptake, may be operative in the fluoxetine-induced remission of the behavioral abnormalities associated with mood disorders [5].
• Substantial evidence links alcohol drinking and serotonin (5-HT) functioning in animals [2].
• These findings have implications for understanding the potential long-term consequences of genetic and pharmacological disruption of 5-HT neurotransmission on cerebral functions during critical periods of postnatal development [6].
• It is suggested that 5-HT represents a dietary responsive endogenous factor regulating predatory behavior in carnivores [7].
• Thus, altered 5-HT innervation and/or uptake in the DMX may contribute to abnormal 5-HT modulation of this major autonomic nucleus in patients with Rett syndrome [8].

High impact information on Htr4

• MAOA preferentially oxidizes serotonin (5-hydroxytryptamine, or 5-HT) and norepinephrine (NE), whereas MAOB preferentially oxidizes beta-phenylethylamine (PEA) [9].
• Injection of anti-ApCREB2 antibodies into Aplysia sensory neurons causes a single pulse of serotonin (5-HT), which induces only short-term facilitation lasting minutes, to evoke facilitation lasting more than 1 day [10].
• The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) elicits a wide array of physiological effects by binding to several receptor subtypes [11].
• However, cerebral 5-HT concentrations then decline due to specific neurotoxic damage to 5-HT nerve endings in the forebrain [12].
• Some recovery of 5-HT stores can be seen within 24 h of MDMA administration [12].

Chemical compound and disease context of Htr4

• We evaluated food intake, body-weight gain, diencephalic NOS activity, and diencephalic content of tryptophan (TRP), 5-HT, hydroxyindoleacetic acid (5-HIAA), and 5-HIAA/5-HT ratio after intracerebroventricular (ICV) or intraperitoneal (IP) leptin injection in mice [13].
• Both 5-HT and 5-carboxamidotryptamine, a 5-HT(1) and 5-HT(7) receptor agonist, in physiological doses fail to induce hypothermia in 5-HT(7) knockout mice [14].
• Taken together, the results show that 5-HT-induced hypothermia is mediated by the 5-HT(7) receptor, and that oleamide may act through an independent mechanism as well as at an allosteric 5-HT(7) receptor site to regulate body temperature [14].
• Together, these data indicate that mice genetically endowed with increased SOD activity are protected from 2'-NH2-MPTP-induced toxicity, thereby implicating superoxide radicals in the mechanism of action of a neurotoxin that selectively depletes 5-HT and NE without affecting dopamine [15].
• To elucidate the molecular and pathophysiologic mechanisms underlying PAF-associated bronchial hyperreactivity, we studied airway responsiveness to methacholine (MCh) and serotonin (5-hydroxytryptamine; 5-HT) in PAFR-transgenic mice [16].

Biological context of Htr4

• These data suggest that both sequestration and phosphorylation by beta ARK, or another specific agonist-dependent receptor kinase, are involved in homologous desensitization of 5-HT4 receptors coupled to adenylyl cyclase [17].
• Using degenerate oligonucleotide primers, we identified a rat brain PCR fragment which encoded a '5-HT receptor-like' amino acid sequence [18].
• The neurotransmitter serotonin (5HT) activates a variety of second messenger signaling systems and through them indirectly regulates the function of ion channels [19].
• Infection-induced up-regulation of 5-HT2A expression was correlated with the smooth muscle hypercontractility to 5-HT [20].
• In addition, molecular biology techniques have provided new tools with which to study the function of 5-HT receptors [21].

Anatomical context of Htr4

• In these brain regions as well as in the hypothalamus, bulbectomy also caused a reduction of the molar ratio of 5-hydroxyindoleacetic acid to serotonin (5-HT) indicating a decrease in 5-HT turnover [22].
• Expression and function of 5-HT4 receptors in the mouse enteric nervous system [23].
• In mouse midbrain and striatal synaptosomes, maximal stimulatory effects on 5-HT uptake occurred at lower concentrations (IL-1beta, 10 ng/ml; TNF-alpha, 20 ng/ml), and over shorter incubation times (10 min) [24].
• MDMA produces an acute, rapid enhancement in the release of both serotonin (5-HT) and dopamine from nerve endings in the brains of experimental animals [12].
• In the current study, light microscopic radioautographs from animals treated with [3H]5-HT indicated that local mast cells released 5-HT between 6 and 18 h during the evolution of DTH [25].

Associations of Htr4 with chemical compounds

• Neurons exposed to other agents, like isoproterenol, vasoactive intestinal peptide, or forskolin, that increase cAMP levels did not undergo any desensitization of 5-HT4 receptors [17].
• When permeabilized neurons were loaded with heparin, an inhibitor of the beta-adrenergic receptor kinase (beta ARK), 5-HT4 receptor desensitization was reduced by 30-40% [17].
• Activation of protein kinase A with either 8-bromo-cAMP or dibutyryl-cAMP or application of inhibitors of protein kinase A-dependent phosphorylation did not change the rate of 5-HT4-induced desensitization [17].
• IL-1beta induced an SB203580-sensitive decrease in 5-HT K(m) with no significant change in V(max) [24].
• Thus, the neurosteroid-induced positive allosteric modulation of GABA action at GABAA receptors is facilitated by fluoxetine or its congeners (i.e., paroxetine, fluvoxamine, sertraline), which may not block 5-HT reuptake at the doses currently prescribed in the clinic [5].

Physical interactions of Htr4

• The potency of benzamides (cisapride greater than BRL 24924 greater than zacopride greater than BRL 20627 greater than metoclopramide) is similar to their effect of 5-HT4 receptors positively coupled with an adenylate cyclase of fetal mouse colliculi neurons [26].
• 5-HT receptor positively coupled to adenylyl cyclase in striatal neurones in culture does not correspond to the 5-HT4 receptor [27].

Regulatory relationships of Htr4

• In RN46A cells, IL-1beta stimulated 5-HT uptake in a dose- and time-dependent manner, peaking in 20 min at 100 ng/ml [24].

Other interactions of Htr4

• 5-HT and 5-HT(1P) agonists evoked a G protein-mediated long-lasting inward current that was neither mimicked by 5-HT(4) agonists nor blocked by 5-HT(4) antagonists [23].
• The C57BLKS/J db/db mouse develops hyperglycemia and has delayed gastric emptying that is improved with tegaserod, a partial 5-HT4 agonist [28].
• In mouse hippocampal neurons, activation of the endogenous 5-HT7 receptors significantly increased neurite length, whereas stimulation of 5-HT4 receptors led to a decrease in the length and number of neurites [29].
• Serotonin-induced contractions were partially inhibited by atropine, the 5-HT4 antagonist GR113808, and the 5-HT2 antagonist cinanseron but not tetrodotoxin [28].
• 5HT1c receptor antagonists (mianserin and cyproheptadine), 5-HT3 receptor antagonist (zacopride) and 5-HT4 receptor antagonist (ICS 205-930) increased the latency of audiogenic seizures and decreased the severity of convulsions in young (20-27 days old) DBA/2 mice [30].

Analytical, diagnostic and therapeutic context of Htr4

• The 5-HT4 receptor: molecular cloning and pharmacological characterization of two splice variants [18].
• Microdialysis sampling during a 10-min FS showed that NA and 5-HT release were elevated to 213% and 156%, respectively, in the GalOE/P group, whereas in the WT group the increases were only 127% and 119%, respectively [31].
• In the present study, we combined receptor binding autoradiography with neurochemical ablation of 5-HT axons or electrolytic lesions of the dorsal thalamus in an effort to determine the neural elements upon which the 5-HT1B receptors were located [32].
• This view is consistent with earlier studies showing that pharmacological activation of the 5-HT system is anxiogenic in animal models and also in humans [33].
• Carbon fiber microelectrodes were used to measure individual secretory events of histamine and 5-hydroxytryptamine (5-HT) from VMAT2-expressing mast cells as a model system for quantal release [34].

References