Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibition of forskolin-stimulated cyclic AMP accumulation was measured in two stable HeLa cell lines HA6 and HA7 expressing different levels of recombinant human 5-HT1A receptors. These cells were studied previously to characterize another second messenger system activated by 5-HT1A receptors, i.e. calcium mobilization. The pharmacological characterization of the inhibition of cyclic AMP accumulation was made using agonists (5-HT, 8-OH-DPAT, buspirone, MDL 73005) and putative antagonists (SDZ 216-525, NAN-190, WAY-100135, pindolol, propranolol, WAY 100635). It is shown that 5-HT, 8-OH-DPAT, buspirone, MDL 73005 behaved as full (or nearly full) and potent agonists, whereas SDZ 216-525, NAN-190 and WAY-100135 displayed a limited (and similar) degree of intrinsic activity at human 5-HT1A receptors; on the other hand pindolol, propranolol and WAY 100635 behaved as "silent" antagonists. The effects were quantitatively and qualitatively very similar in both cells lines for all drugs tested, suggesting that the coupling between 5-HT1A receptors and inhibition of cyclic AMP accumulation in HeLa cells is very tight. There were, however, significant variations in both the level of agonism and the potency of a number of compounds when calcium mobilization and the inhibition of cyclic AMP accumulation were compared. Especially in HA7 cells which express lower receptor levels, a number of drugs failed to display agonism (e.g. buspirone or MDL 73005), whereas in HA6 cells they acted as partial agonists. Together, the data show that functional responses mediated by the same receptor can vary rather dramatically depending on receptor density and/or on the effector system involved. Interestingly, 5-HT1A receptor-mediated inhibition of adenylate cyclase activity measured in calf hippocampal membranes shows very similar degrees of potency and intrinsic activity for a number of compounds that have been tested on the inhibition of cyclic AMP accumulation in HeLa cells, suggesting that the very tight coupling observed in the recombinant system may apply to native 5-HT1A receptors.
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PMID:Inhibition of cAMP accumulation via recombinant human serotonin 5-HT1A receptors: considerations on receptor effector coupling across systems. 922 66

The regulation by N-methyl-D-aspartate (NMDA) and 5-HT1A receptors of the endogenous gamma-aminobutyric acid (GABA) release was investigated in slices of the guinea pig dentate gyrus. The release of GABA was increased in a concentration-dependent fashion by NMDA. The release of GABA evoked by NMDA was Ca2+-dependent, tetrodotoxin-resistant, Mg2+-sensitive and inhibited by MK-801, a selective non-competitive NMDA receptor antagonist. These results suggest that the NMDA receptor present on GABAergic neurons is involved in the stimulatory regulation of GABA release. The release of GABA was increased concentration-dependently by NAN-190, a 5-HT1A receptor antagonist, but was not affected by 8-OH-DPAT, a 5-HT1A receptor agonist. The release of GABA evoked by NAN-190 was Ca2+-dependent, tetrodotoxin-resistant and inhibited by 8-OH-DPAT. These results suggest that the 5-HT1A receptor present on GABAergic neurons is involved in the inhibitory regulation of GABA release. The release of GABA evoked by NMDA from the dentate gyrus was inhibited by pretreatment with 8-OH-DPAT. The release of GABA evoked by NAN-190 was inhibited by pretreatment with MK-801. The release of GABA evoked by NMDA from the dentate gyrus was augmented by the concurrent application of NAN-190. Taken together, the results indicate that the NMDA receptor and the 5-HT1A receptor, which are both located on GABAergic neurons in the guinea pig dentate gyrus, exert stimulatory and inhibitory regulation of neuronal GABA release, respectively.
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PMID:Regulation of GABA release via NMDA and 5-HT1A receptors in guinea pig dentate gyrus. 924 72

The primary sensory Rohon-Beard (R-B) neurons of Xenopus larvae are highly analogous to the C fibers of the mammalian pain pathway. We explored the actions of 5-HT by studying the modulation of Ca2+ currents. In approximately 80% of the acutely isolated R-B neurons, 5-HT inhibited the high voltage-activated (HVA) currents by 16% (n = 29) and the T-type currents by 24% (n = 41). The modulation of the T-type and the HVA currents was mimicked by selective 5-HT1A and 5-HT1D agonists: 8-OH-DPAT and L-694,247. The effects of the agonists were blocked by their respective 5-HT1A or 5-HT1D antagonists: p-MPPI and GR127935, suggesting that both 5-HT1A and 5-HT1D receptors were involved. Approximately 70% of the actions of 5-HT on HVA currents was occluded by omega-conotoxin-GVIA (N-type channel blocker), whereas the rest of the modulation ( approximately 30%) was occluded by <100 nM omega-agatoxin-TK (P/Q-type channel blocker). This suggests that 5-HT acts on N- and P/Q-type Ca2+ channels. Neither the modulation of the T-type nor that of the HVA currents was accompanied by changes in their voltage-dependent kinetics. Cell-attached patch-clamp recordings suggest that the modulation of the T-type channel occurs through a membrane-delimited second messenger. We have studied the functional consequences of the modulation of T-type Ca2+ channels and have found that these channels play a role in spike initiation in R-B neurons. Modulation of T-type channels by 5-HT therefore could modulate the sensitivity of this sensory pathway by increasing the thresholds of R-B neurons. This is a new and potentially important locus for modulation of sensory pathways in vertebrates.
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PMID:Serotonergic inhibition of the T-type and high voltage-activated Ca2+ currents in the primary sensory neurons of Xenopus larvae. 927 19

Isradipine and darodipine are dihydropyridine calcium antagonists that affect the serotonergic pathways with a peculiar profile of effects because, at low dose (0.08 and 0.3 mg/kg, respectively) they facilitate, but at high dose (1.60 and 5.0 mg/kg, respectively) they inhibit the serotonergic neurotransmission. To investigate the mechanisms of these effects, the selective 5-HT1A receptor agonist 8-OHDPAT was injected S.C. to rats pretreated I.P. with isradipine (0.04-1.60 mg/kg) or darodipine (0.3-5.0 mg/kg). By stimulating presynaptic 5-HT1A autoreceptor, 8-OHDPAT induced signs of inhibition of the serotonergic neutransmission (i.e., decrease of the 5-HIIA/5-HT ratio), but it also produced behavioral effects by stimulating postsynaptic 5-HT1A receptors (i.e., forepaw treadings). A low dose of isradipine (0.08 mg/kg) or darodipine (0.3 mg/kg) antagonized the presynaptic, but enhanced the postsynaptic effects of 8-OHDPAT, suggesting relief of the autoreceptor-mediated inhibition of the 5-HT release. Thus, the amine released could stimulate postsynaptic receptors, adding its action to that of 8-OHDPAT. A high dose of isradipine (1.60 mg/kg) or darodipine (5.0 mg/kg) left unchanged, or also enhanced, the signs of inhibition of serotonergic neurotransmission displayed by 8-OHDPAT, reducing but not suppressing the increase in the behavioral response to the stimulation of postsynaptic 5-HT1A receptors. It was speculated that the effects of isradipine and darodipine on scrotonergic pathways of rat brain could be due to changes in the back-regulation of the neurotransmission, mediated by 5-HT1A autoreceptors. This mechanism of action could be extended to other dihydropyridine calcium antagonists, because blockade of L-type VSCC by these compounds appears to be involved in their effects on brain 5-HT turnover.
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PMID:Interactions between darodipine or isradipine and the 5-HT1A receptor agonist 8-OHDPAT in rat brain. 930 May 83

Little is definitively known of the identity or actions of neurotransmitters utilized within mammalian taste buds. Serotonin has been immunocytochemically localized to taste cells of several species but its physiological actions are unknown. Using whole-cell patch clamp recordings on dissociated posterior rat taste cells, data are presented to suggest that exogenously applied serotonin inhibits a calcium-activated potassium current by up to 50%. This current, best visualized at depolarized holding potentials, is both apamin- and charybdotoxin-sensitive. Approximately 60% of the tested taste cells were serotonin sensitive. This inhibition was mimicked by N-(3-trifluoromethylphenyl)piperazine (TFMPP), a general serotonin receptor agonist, by 8-hydroxy-dipropylaminotetralin (8-OH-DPAT), a selective 5-HT1A receptor agonist, but not by phenylbiguanide, a 5-HT3 receptor agonist. These are the first data to establish a physiological effect of serotonin on mammalian taste cells.
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PMID:Serotonin inhibits calcium-activated K+ current in rat taste receptor cells. 935 53

Serotonin acts on 5-hydroxytryptamine (5-HT)1B-like receptors in isolated rabbit ear artery precontracted with phenylephrine (PHE). These receptors are inactive, or "silent," in untreated vessels. Ear artery rings were mounted in tissue baths for the measurement of isometric contraction to further characterize these 5-HT1B-like receptors. The 5-HT1-selective receptor agonist sumatriptan failed to contract the untreated ear artery rings but caused a powerful, concentration-dependent contraction in PHE-precontracted vessels. The 5-HT1A/rat 1B receptor antagonist propranolol (1 microM) had no effect, whereas the 5-HT1B receptor antagonists rauwolscine (0.1 microM) and GR127935 (1-100 nM) markedly inhibited the contraction to sumatriptan. In vessels precontracted with phenylephrine, nifedipine reduced and calcium-free medium abolished the contractile response to serotonin. Relaxation to the adenylate cyclase activator forskolin was studied in contracted ear artery rings. Low concentrations (0.1-0.3 microM) of forskolin rapidly and completely relaxed ear artery rings contracted with PHE. In contrast, when PHE-precontracted vessels were contracted with either serotonin or sumatriptan, forskolin caused little or no relaxation at low concentrations and only partial relaxation at 10- to 30-fold higher concentrations. The resistance of these vessels to relaxation by forskolin was markedly reduced in the presence of GR127935 or in ear artery rings from pertussis toxin-treated rabbits. However, pertussis toxin treatment had no effect on the contractile response of PHE-precontracted ear artery rings to serotonin. It is concluded that the silent 5-HT1-like receptor of rabbit ear artery closely resembles the 5-HT1B receptor subtype. This receptor is inversely coupled to adenylate cyclase through a pertussis toxin-sensitive G protein; however, this coupling is unlikely to contribute to the serotonin-induced contraction of PHE-precontracted ear artery rings. Instead, this contraction is mediated at the second-messenger level by pertussis toxin-insensitive influx of calcium.
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PMID:Pharmacological characterization of the "silent" 5-hydroxytryptamine1B-like receptors of rabbit ear artery. 935 82

1. The release of glutamic acid and its modulation by 5-hydroxytryptamine (5-HT) in the human brain has been investigated in synaptosomal preparations from fresh neocortical samples obtained from patients undergoing neurosurgery to reach deeply sited tumours. 2. The Ca2+-dependent K+ (15 mM)-evoked overflow of glutamate was inhibited by 5-HT in a concentration-dependent manner (EC50 = 2.9 nM; maximal effect approximately 50%). The inhibition caused by 5-HT was antagonized by the 5-HT1/5-HT2 receptor antagonist methiothepin. The 5-HT1B/5-HT1D receptor agonist sumatriptan mimicked 5-HT (EC50 = 6.4 nM; maximal effect approximately 50%); the effect of sumatriptan was also methiothepin-sensitive. Selective 5-HT1A receptor antagonists could not prevent the inhibition of glutamate release by 5-HT. 3. The 5-HT1B/5-HT1D receptor ligand GR 127935 and the 5-HT2C/5-HT1B/5-HT1D receptor ligand metergoline were unable to prevent the 5-HT effect; instead they inhibited glutamate release, their effects being abolished by methiothepin. Some 5-HT1A receptor antagonists also displayed intrinsic agonist activity. 4. The effect of sumatriptan was prevented by ketanserin, a drug known to display much higher affinity for recombinant h 5-HT1D than for h 5-HT1B receptors. 5. We propose that neocortical glutamatergic nerve terminals in human brain cortex possess release-inhibiting presynaptic heteroreceptors that appear to belong to the h 5-HT1D subtype.
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PMID:Glutamate release in human cerebral cortex and its modulation by 5-hydroxytryptamine acting at h 5-HT1D receptors. 948 53

1. In whole-cell patch clamp recordings made from non-sensory neurons acutely isolated from the spinal cord of Xenopus (stage 40-42) larvae, two forms of inhibition of the high voltage-activated (HVA) Ca2+ currents were produced by 5-HT. One was voltage dependent and associated with both slowing of the activation kinetics and shifting of the voltage dependence of the HVA currents. This inhibition was relieved by strong depolarizing prepulses. A second form of inhibition was neither associated with slowing of the activation kinetics nor relieved by depolarizing prepulses and was thus voltage independent. 2. In all neurons examined, 5-HT (1 microM) reversibly reduced 34 +/- 1.6 % (n = 102) of the HVA Ca2+ currents. In about 40 % of neurons, the inhibition was totally voltage independent. In another 5 %, the inhibition was totally voltage dependent. In the remaining neurons, inhibition was only partially (by around 40 %) relieved by a large depolarizing prepulse, suggesting that in these, the inhibition consisted of both voltage-dependent and -independent components. 3. By using selective channel blockers, we found that 5-HT acted on both N- and P/Q-type channels. However, whereas the inhibition of P/Q-type currents was only voltage independent, the inhibition of N-type currents had both voltage-dependent and -independent components. 4. The effects of 5-HT on HVA Ca2+ currents were mediated by 5-HT1A and 5-HT1D receptors. The 5-HT1A receptors not only preferentially caused voltage-independent inhibition, but did so by acting mainly on the omega-agatoxin-IVA-sensitive Ca2+ channels. In contrast, the 5-HT1D receptor produced both voltage-dependent and -independent inhibition and was preferentially coupled to omega-conotoxin-GVIA sensitive channels. This complexity of modulation may allow fine tuning of transmitter release and calcium signalling in the spinal circuitry of Xenopus larvae.
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PMID:Differential inhibition of N and P/Q Ca2+ currents by 5-HT1A and 5-HT1D receptors in spinal neurons of Xenopus larvae. 962 70

Experiments were carried out to determine the effects of altering the serotonin (5-HT) levels in the hypothalamus on thermoregulatory function in unanesthetized restrained rats. Local perfusion of the hypothalamus with dialysis solution containing 5-hydroxytryptophan (a 5-HT precursor), fluoxetine (a 5-HT reuptake inhibitor), or high potassium significantly increased both colonic temperature (Tco) and the extracellular concentrations of 5-HT in the hypothalamus. Reciprocally, both extracellular concentration of 5-HT in the hypothalamus and Tco were decreased with a dialysis solution containing tetrodotoxin (which blocks the voltage-dependent sodium channel), zero calcium concentration, or systemic administration of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT,5-HT1A agonist). Intrahypothalamic administration of 8-OH-DPAT and (2,5-dimethoxy-4-iodophenyl)-2-aminopropane (a 5-HT2 agonist) produced hypothermic and hyperthermic effects, respectively. The results indicate that elevating the 5-HT levels in the hypothalamus activates postsynaptic 5-HT2 receptors and results in hyperthermic effects, whereas stimulation of presynaptic 5-HT1A receptors in the hypothalamus reduces the endogenous 5-HT release and results in hypothermic effects.
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PMID:Changes in extracellular serotonin in rat hypothalamus affect thermoregulatory function. 964 38

3, 4-methylenedioxymethamphetamine (MDMA or Ecstasy) is a substituted amphetamine whose acute and long-term effects on the serotonin system are dependent on an interaction with the 5-HT uptake transporter (SERT). Although much of the work dedicated to the study of this compound has focused on its ability to release monoamines, this drug has many important metabolic consequences on neurons and glial cells. The identification of these physiological responses will help to bridge the gap that exists in the information between the acute and neurotoxic effects of amphetamines. Substituted amphetamines have the ability to produce a long-term translocation of protein kinase C (PKC) in vivo, and this action may be crucial to the development of serotonergic neurotoxicity. Our earlier results suggested that PKC activation occurred through pre- and postsynaptic mechanisms. Because the primary site of action of these drugs is the 5-HT transporter, we now expand on our previous results and attempt to characterize MDMA's ability to translocate PKC within cortical 5-HT nerve terminals. In synaptosomes, MDMA produced a concentration-dependent increase in membrane-bound PKC (as measured by 3H-phorbol 12, 13 dibutyrate, 3H-PDBu) bindings sites. This response was abolished by cotreatment with the specific serotonin reuptake inhibitor (SSRI), fluoxetine, but not by the 5-HT2A/2C antagonist, ketanserin. In contrast, full agonists to 5-HT1A and 5-HT2 receptors did not produce significant PKC translocation. MDMA-mediated PKC translocation also requires the presence of extracellular calcium ions. Using assay conditions where extracellular calcium was absent prevented in vitro activation of PKC by MDMA. Prolonged PKC translocation has been hypothesized to contribute to the calcium-dependent neurotoxicity produced by substituted amphetamines. In addition, many physiological processes within 5-HT nerve terminals, including 5-HT reuptake and vesicular serotonin release, are susceptible to modification by PKC-dependent protein phosphorylation. Our results suggest that prolonged activation of PKC within the 5-HT nerve terminal may contribute to lasting changes in the homeostatic function of 5-HT neurons, leading to the degeneration of specific cellular elements after repeated MDMA exposure.
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PMID:Characterization of the translocation of protein kinase C (PKC) by 3,4-methylenedioxymethamphetamine (MDMA/ecstasy) in synaptosomes: evidence for a presynaptic localization involving the serotonin transporter (SERT). 971 90


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