UNIPROT:P08908 - FACTA Search

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)

The binding of [3H]8-hydroxy-2-(di-N-propylamino)-tetralin ([ 3H]8-OH-DPAT) to rat hippocampal and striatal membranes has been compared. In the hippocampus, low concentrations of [3H]8-OH-DPAT bound to a single, high affinity site which was sensitive to inhibition by spiperone, buspirone and ergotamine but not by mianserin, quipazine or (-)-propranolol. This is consistent with a selective labeling of the 5-HT1A receptor. In the striatum, [3H]8-OH-DPAT bound to two sites with high and low affinity (KD's 1.18 and 109 nM). The high affinity component was blocked by low concentrations of buspirone, spiperone and ergotamine. The low affinity component was blocked only by high concentrations of buspirone and spiperone, and was not displaced by ergotamine at concentrations up to 1 microM. The ergotamine-resistant component of striatal [3H]8-OH-DPAT binding was blocked by low concentrations of the 5-HT uptake inhibitors fluvoxamine and paroxetine, and by relatively low concentrations of 5-HT itself. Thus [3H]8-OH-DPAT labels the 5-HT transporter in the rat striatum. Unlike [3H]imipramine binding, the binding of [3H]8-OH-DPAT to the 5-HT transporter was independent of external sodium ions. It is therefore suggested that 8-OH-DPAT acts as substrate for the 5-HT transporter and labels the 5-HT recognition site of the transporter complex.
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PMID:[3H]8-OH-DPAT labels the 5-hydroxytryptamine uptake recognition site and the 5-HT1A binding site in the rat striatum. 290 86

Organotypic cultures of fetal mouse spinal cord-ganglion explants (2-4 weeks in vitro) contain forskolin-stimulated adenylate cyclase (AC) activity that is inhibited by levorphanol and other opioid agonists in a dose-dependent manner. Inhibition by levorphanol no longer occurs if sodium is omitted from the incubation and the levorphanol inhibition is blocked by the opioid antagonist, naloxone. These findings together with the ineffectiveness of dextrorphan indicate that the opioid inhibition of forskolin-stimulated AC is receptor mediated. Both the delta- and kappa-receptor subtypes appear to be involved since the selective delta-opioid agonist, [D-Pen2, D-Pen5]enkephalin, and the selective kappa-opioid agonist, t-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl)cyclohexyl]-benzene acetamide (U-50,488H) are both effective at nanomolar concentrations. In contrast, the selective mu-opioid agonist, Tyr-D-Ala-Gly-N-MePhe-Gly-ol, has no significant effect even at micromolar concentrations. Both cord and ganglion components of the explants contain opioid-sensitive AC. Forskolin-stimulated AC of the explants is also inhibited by serotonin and carbachol. The serotonin effect appears to be mediated by 5-HT1A receptors, based on relative agonist and antagonist selectivity. Chronic exposure of cultures to morphine results in enhanced basal and forskolin-stimulated AC as well as attenuation of opioid-inhibition of AC assayed in the presence of forskolin; treatment of explants with pertussis toxin causes similar changes in the AC system. The inhibitory effect of serotonin is also attenuated by the pertussis toxin treatment. Basal AC activity of the explants (assayed without forskolin present) is stimulated to a small but significant extent by opioids and by serotonin. The opioid stimulatory effect is markedly enhanced following either morphine or pertussis toxin treatment of the explants. The attenuation of opioid- and serotonin-inhibition of AC produced by chronic exposure to pertussis toxin and the attenuation of opioid inhibition produced by exposure to morphine are consonant with the attenuation of opioid and monoaminergic depression of sensory evoked dorsal horn network responses after similar chronic treatments. It is proposed that the inhibitory effects of opioids and serotonin on these neurons are mediated by receptors that are negatively coupled via a pertussis toxin sensitive Gi protein to AC. Furthermore, alterations of AC with chronic morphine treatment may be involved in the development of physiologic tolerance to opioids.
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PMID:Modulation of adenylate cyclase activity of mouse spinal cord-ganglion explants by opioids, serotonin and pertussis toxin. 337 Apr 65

The synthesis of a tritiated derivative of the 5-HT1A photoaffinity probe 8-methoxy-2-[N-n-propyl, N-3-(2-nitro-4-azidophenyl)aminopropyl]aminotetralin ([3H]8-methoxy-3'-NAP-amino-PAT) allowed the use of this probe for attempting the irreversible labeling of specific binding sites in rat brain membranes. Sodium dodecyl-sulfate-polyacrylamide gel electrophoresis of proteins solubilized from hippocampal microsomal membranes that had been incubated with 20 nM [3H]8-methoxy-3'-NAP-amino-PAT under UV light revealed a marked incorporation of 3H label into a 63-kilodalton protein termed PI. As expected of a possible correspondence between PI and 5-HT1A receptor binding sites, 3H labeling by the photoaffinity probe could be prevented by selective 5-HT1A ligands such as 8-hydroxy-2-(di-n-propylamino)tetralin, ipsapirone, buspirone, and gepirone and by N-ethylmaleimide, but not by the 5-HT2 antagonist ketanserin, noradrenaline- and dopamine-related drugs, monoamine oxidase inhibitors, and chlorimipramine. Furthermore, the regional and subcellular distributions of PI were identical to those of specific 5-HT1A binding sites. These results indicated that the binding subunit of the 5-HT1A receptor is a 63-kilodalton protein with a functionally important sulfhydryl group(s).
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PMID:Identification of the 5-HT1A receptor binding subunit in rat brain membranes using the photoaffinity probe [3H]8-methoxy-2-[N-n-propyl, N-3-(2-nitro-4-azidophenyl)aminopropyl]aminotetralin. 359 78

Membrane proteins are typically extracted by detergent concentrations of 0.5-2.0%, using detergent/protein ratios of 1:1 to 3:1. We have compared the ability of 14 different detergents from seven different structural and ionic classes, at a concentration of 2.0% and a detergent/protein ratio of 2:1, to extract an integral membrane protein (the serotonin 5-HT1A receptor) in active form and have observed profound differences in both lipids and proteins. All extracts were freed from detergents and dialyzed to form vesicles containing 95-100% of the extracted lipids, prior to [3H]8-hydroxy-2-(N,N-di-n-propylamino)tetralin ([3H]8-OH-DPAT) binding. The most efficient detergents in extracting active 5-HT1A receptor protein were the zwitterionic 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) and 3-[(cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate (CHAPSO), followed by the neutral n-dodecyl-beta-D-maltoside. Zwitterionic detergents also produced the highest solubilized lipid/protein ratio (3.0 and 2.5, respectively) and in general the relative amounts of extracted lipids and proteins followed inverse profiles. Thus, hydrophobic detergents such as Tritons (with critical micelle concentrations similar to CHAPS) and Thesit (structurally similar to Lubrol) extracted the most protein, but relatively little lipid (ratios of less than 0.2) and very little active 5-HT receptor. Dramatic differences were also observed in the ratios of individual lipids extracted by the same concentrations of different detergents and resolved by high-performance thin-layer chromatography. For example, galactosylceramide (GalCer) content ranged from 2.7% (CHAPSO) to 13.4% (sodium cholate) of the total lipid extract and cholesterol ranged from 0% (digitonin) to 17.9% (Triton X-100). The detergent-extractability profile for phosphatidylethanolamine (PE) (range 15-40% of total lipid) paralleled that of phosphatidylinositol (PI) (range 4-10%), but was inverse to that for GalCer and cholesterol. Detergent-extractability profiles for phosphatidylcholine (PC) and phosphatidylserine (PS) also followed inverse profiles, with zwitterionic detergents giving high PS/PC and high PE/PC ratios (approximately 2:1), whereas the Tritons and digitonin gave ratios of 1:2. We believe that differential solubilization of lipids, as well as proteins, by detergents is important for the biological activity of the extracted proteins, and lipid extractability should be taken into account when purifying membrane proteins.
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PMID:Differential solubilization of lipids along with membrane proteins by different classes of detergents. 758 93

This study was performed in rats to determine if serotonin and its receptors are involved in the increase of gastric emptying (GE) induced by benzodiazepine (BZ) withdrawal. GE was measured with a test meal (2 ml) containing 1 microCi/ml of 51Cr sodium chromate administered in rats, either previously receiving injections with diazepam (15 mg/kg/day i.p.) or with DMSO (0.9 ml/day i.p.) during 7 days. On the 8th day, animals received the different serotonin (5-HT) agonists or antagonists, and flumazenil (BZ antagonist; 15 mg/kg i.p.) 30 and 15 min, respectively, before the test meal. Methiotepin (5-HT1 antagonist) either i.p. (0.1-1 mg/kg) or intracerebroventricularly (10 micrograms/kg) had no effect on the increase of GE induced by precipitated-withdrawal. 8-OH-DPAT (5-HT1A agonist) administered i.c.v. (1-10 micrograms/kg) dose dependently reduced GE increase. Administered i.p. (0.1 mg/kg), it blocked GE increase in control and diazepam-withdrawn rats. Ritanserin (5-HT2 antagonist) antagonized GE increase only when administered i.p. (0.1 mg/kg). Granisetron (5-HT3 antagonist) was active both i.p. (0.01-0.1 mg/kg) and intracerebroventricularly (1-10 micrograms/kg). Administered intracerebroventricularly (1 microgram/kg) in diazepam-treated rats, 5-HTP mimicked the effect of flumazenil. It is concluded that diazepam-withdrawal increases GE by stimulating central release of 5-HT and/or central activation of 5-HT neurons. At least central 5-HT3 receptors, and in less extend, peripheral 5-HT2 receptors are involved in this mechanism.
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PMID:Benzodiazepine-withdrawal-induced gastric emptying disturbances in rats: evidence for serotonin receptor involvement. 779 Nov 33

1 The present study compares the effects on representative autonomic outflows of IVth ventricular application of tryptamine analogues which act at 5-HT1 receptors with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). 2 Cumulative doses of 8-OH-DPAT, N,N-di-n-propyl-5-carboxamidotryptamine (DP-5-CT) and 5-carboxamidotryptamine (5-CT, 2.5-40 nmol kg-1), sumatriptan (10-160 nmol kg-1), indorenate (100-800 nmol kg-1), 5-hydroxytryptamine (5-HT, 20-640 nmol kg-1) both alone and in the presence of cinanserin (0.1 mg kg-1) were given into the IVth ventricle of cats which were anaesthetized with a mixture of alpha-chloralose and pentobarbitone sodium, neuromuscularly blocked and artificially ventilated. Recordings were made of arterial blood pressure, heart rate, renal, cardiac, splanchnic and phrenic nerve activities, femoral arterial flow, tracheal and intragastric pressures. 3 Central application of each of the agonists evoked significant falls in arterial blood pressure. In addition 8-OH-DPAT, DP-5-CT, 5-CT and 5-HT all evoked a differential inhibition of sympathetic nerve activities, with renal nerve activity being the most sensitive and cardiac nerve activity the least sensitive. In the dose-ranges used, administration of sumatriptan evoked reductions only in renal and splanchnic nerve activities whilst indorenate reduced activity in all three sympathetic nerves to a similar extent. 4. The effect of the agonists on heart rate was more inconsistent than the effects on sympathetic outflow.IVth ventricular application of 5-CT and sumatriptan were without effect on heart rate whilst 8-OH-DPAT, DP-5-CT, indorenate and 5-HT alone and in the presence of cinanserin all evoked significant bradycardias. However, whilst atropine partially reversed the bradycardias evoked by 8-OHDPAT and only slightly reversed those caused by indorenate, atropine was without effect on those evoked by DP-5-CT or 5-HT.5. None of the analogues tested had significant effects on gut motility, phrenic nerve discharge or tracheal pressure. 8-OH-DPAT, DP-5-CT, indorenate and 5-HT were without effect on femoral arterial conductance. However, following pretreatment with cinanserin, 5-HT evoked a significant reduction in femoral arterial conductance. At its highest dose, sumatriptan evoked a significant increase in femoral arterial conductance as did 5-CT at the 20 nmol kg-1 dose.6. It is concluded that the present data support the view that 5-HT1A receptors at the level of the brainstem are involved in the central sympathoinhibitory effects caused by intravenous administration of 5-HT1A agonists. Further, brainstem 5-HT1A receptors play an important role in the control of renal sympathetic outflow while brainstem 5-HT2 receptors are involved in the control of skeletal muscle and/or skin blood flow. Selective tryptamine agonists for 5-HT1A receptors differ from non-tryptamine agonists in that they do not cause an increase in central cardiac vagal tone.
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PMID:Comparison of the effects of IVth ventricular administration of some tryptamine analogues with those of 8-OH-DPAT on autonomic outflow in the anaesthetized cat. 800 5

1. The present study was designed to examine the effects of a centrally acting 5-HT1A receptor agonist, flesinoxan, on the cardiovascular system and renal haemodynamics and excretory function. 2. In chloralose-urethane anaesthetized Wistar rats, i.v. administration of bolus doses of flesinoxan, at 30, 100, 300 and 1000 micrograms kg-1, caused significant, dose-dependent decreases in mean arterial pressure, of 33 +/- 2 mmHg (P < 0.001) and heart rate of 57 +/- 9 beats min-1 (P < 0.001) at the highest dose used. Despite this substantial fall in perfusion pressure there were no meaningful changes in the renal excretion of water and sodium. In a second group of rats, reduction of renal perfusion pressure mechanically to the same values as observed in rats given flesinoxan (i.e. 100, 92, 84 and 76 mmHg) produced reductions in urine flow, absolute and fractional sodium excretions reaching a maximum of 74, 86 and 84% respectively (all P < 0.001) at the lowest pressure. These reductions were significantly larger than those seen in the previous group of animals. 3. In the group of rats subjected to renal denervation, flesinoxan produced changes in blood pressure and heart rate which were not different from those observed in intact animals. However, the reduction in pressure was accompanied by significant decreases in urine flow of 71%, absolute sodium excretion of 68% and fractional sodium excretion of 67% (all P < 0.001) at the highest dose, which were all significantly greater than the changes seen in the innervated animals but were not different from those observed when renal perfusion pressure was reduced mechanically. 4. The findings of this investigation showed that flesinoxan was effective in lowering blood pressure and heart rate in the anaesthetized rat, which was probably due to decreased sympathetic nerve activity.Renal excretion of water and sodium was well preserved in the face of the flesinoxan-induced hypotension.The maintenance of fluid excretion with flesinoxan appeared to be mediated via changes in renal nerve activity, since it did not occur when the kidney was denervated.
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PMID:The renal functional responses to 5-HT1A receptor agonist, flesinoxan, in anaesthetized, normotensive rat. 803 44

Malfunction of inhibitory synaptic processes in the brainstem result in abnormal prolonged inspiration (apneusis). Since we previously found that the serotonin (5-hydroxytryptamine; 5-HT) 5-HT1A receptor agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) shortens inspiratory discharges, we tested its ability to suppress apneusis. We recorded phrenic nerve activity and the membrane potential of medullary expiratory (E-2) and postinspiratory (PI) neurons in 14 anaesthetized, paralyzed, artificially ventilated cats. Systemic hypoxia or i.v. injection of pentobarbital sodium or the N-methyl-D-aspartate (NMDA) receptor blocker ketamine induced apneustic phrenic nerve discharges, delayed depolarization to threshold of E-2 neurons and prolonged hyperpolarization in PI neurons. 8-OH-DPAT (10-40 micrograms/kg i.v.) produced partial to complete restoration of normal phrenic nerve discharges and membrane potential.
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PMID:Serotonin 1A-receptor activation suppresses respiratory apneusis in the cat. 808 36

The present study examined the effects of a centrally acting 5-HT1A receptor agonist flesinoxan on the renal sympathetic nerve control of the kidney while left renal perfusion pressure (RPP) was controlled at 80 mm Hg. In groups of chloralose/urethane-anesthetized Wistar rats, reduction in left kidney RPP significantly decreased the glomerular filtration rate (GFR), with much larger decreases in urine flow (UV) and absolute (UNaV) and fractional (FENa) sodium excretions, but raised systemic pressure as well as right kidney GFR and water and sodium excretion. In intact time-control rats, there were no time-dependent changes in left or right kidney GFR, UV, UNaV or FENa. Administration of bolus doses of flesinoxan at 30, 100 and 300 micrograms/kg i.v. in intact rats caused significant, dose-dependent decreases in mean systemic arterial pressure (23%) and heart rate (10%) (both P < .001). Although RPP was unchanged, there were significant increases in left kidney UV (118%), UNaV (385%) and FENa (277%) (all P < .005). Despite the substantial decrease in RPP at the right kidney, excretion of water and sodium was well preserved. In bilaterally renal-denervated rats, flesinoxan produced similar changes in blood pressure and heart rate but did not increase left kidney UV or sodium excretion, and the reduction in pressure caused significant decreases in right kidney UV, UNaV and FENa. These findings are consistent with the hypothesis that flesinoxan causes suppression of renal sympathetic tone, which leads to increased sodium and water excretion.
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PMID:Renal functional responses to the 5-HT1A receptor agonist flesinoxan: effects of controlled renal perfusion pressure. 816 28

In order to develop tracers with higher specific activity to supplant the currently used [3H]-8-OH-DPAT [8-hydroxy-2-(N,N-di-n-propylamino)tetralin] for in vitro and in vivo evaluation of 5-HT1A receptors, a new radioiodinated ligand was prepared. (R,S)-trans-8- Hydroxy-2-[N-n-propyl-N-(3'-iodo-2'-propenyl)amino]tetralin (trans-8-OH-PIPAT), 8, was synthesized by a 10-step reaction. Binding studies with rat hippocampal membrane homogenates showed that 8 exhibited a Ki value of 0.92 nM against (R,S)-[3H]-8-OH-DPAT. Radiolabeled [125I]-8 was prepared from the corresponding tri-n-butyltin precursor via an oxidative iododestannylation reaction with sodium [125I]iodide. Binding studies in the hippocampal homogenates revealed that [125I]-8 bound to a single high-affinity site (Kd = 0.38 +/- 0.03 nM,Bmax = 310 +/- 20 fmol/mg of protein). Competition binding experiments clearly indicated that the new ligand displayed the expected 5-HT1A receptor binding profile. The rank order of potency was (R,S)-trans-8-OH-PIPAT > (R,S)- 8-OH-DPAT > WB4101 > 5-HT > (R,S)-trans-7-OH-PIPAT > (R,S)-7-OH-DPAT > (R,S)-propranolol > spiperone >> ketanserin >> dopamine > atropine. This new ligand offers several unique advantages, including high specific activity, high binding affinity, and low nonspecific binding, all of which make it an excellent probe for the investigation and characterization of 5-HT1A receptors.
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PMID:Synthesis of (R,S)-trans-8-hydroxy-2-[N-n-propyl-N-(3'-iodo-2'-propenyl)amino]tetral in (trans-8-OH-PIPAT): a new 5-HT1A receptor ligand. 823 Jan 2

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