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)

1. Current and voltage recordings were made from antidromically identified motoneurones (MNs) in transverse thoracolumbar spinal cord slices of neonatal rats. 2. Applied by superfusion (10-100 microM) or pressure ejection, 5-hydroxytryptamine (5-HT) elicited a slow depolarization (or inward current) in 81% and a hyperpolarization (or outward current) in 9% of responsive MNs; the responses persisted in a low-Ca2+, high-Mg2+ or tetrodotoxin (TTX)-containing solution. 3. 5-HT induced the occurrence in some MNs of excitatory postsynaptic potentials (EPSPs) or inhibitory postsynaptic potentials (IPSPs), which were reversibly eliminated by TTX, low-Ca2+, high-Mg2+ solution or by the 5-HT2 receptor antagonists ketanserin and spiperone. Also, kynurenic acid and strychnine abolished, respectively, the 5-HT-induced EPSPs and IPSPs. 4. The 5-HT depolarization was associated with increased membrane resistance, was reduced by hyperpolarization and nullified near -100 mV. The extrapolated reversal potential was shifted to a positive direction in elevated [K+]o. 5. The depolarizing response was mimicked by the 5-HT2 receptor agonist (+2-)-1(2,5-dimethyoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) and blocked by 5-HT antagonists methysergide and cyproheptadine and by 5-HT2 antagonists ketanserin and spiperone; methiothepin and MDL 72222 were without effect. 6. The 5-HT hyperpolarization was associated with decreased membrane resistance. The 5-HT1A agonist 8-hydroxy-2-(di-N-propylamino) tetralin hydrobromide (8-OH-DPAT) mimicked the hyperpolarizing response. 7. Single or repetitive (10-30 Hz) electrical stimuli elicited in about 30% of MNs, in addition to a fast EPSP, a slow EPSP with electrophysiological characteristics similar to that of 5-HT induced depolarization. Methysergide and spiperone abolished the slow EPSPs evoked in some of these MNs. 8. It is suggested that 5-HT, acting on 5-HT2 and 5-HT1A receptors, depolarizes and hyperpolarizes the MNs by decreasing and increasing K+ conductance. Additionally, 5-HT activates, via 5-HT2 receptors, excitatory and inhibitory interneurones, thereby indirectly affecting the activity of MNs. More importantly, 5-HT released from intraspinal nerves appears to be the mediator of a slow EPSP in a population of MNs.
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PMID:5-Hydroxytryptamine responses in neonate rat motoneurones in vitro. 215 Aug 62

Agonist occupancy of the cloned human serotonin (5-HT)1A receptor expressed in HeLa cells stimulates Na+/K+ ATPase activity as assessed by rubidium uptake. The purpose of the study was to determine which of the receptor-associated signaling mechanisms was responsible for this effect. 5-HT stimulated Na+/K+ ATPase 38% at 2 mM extracellular potassium, an effect characterized by a decrease in apparent K0.5 from 2.8 +/- 0.3 to 1.8 +/- 0.3 mM potassium without a significant change in apparent Vmax. The EC50 for the transport effect was approximately 3 microM 5-HT. The response was pertussis toxin-sensitive but did not involve inhibition of adenylate cyclase, as stimulation of Na+/K+ ATPase by 5-HT was observed in the presence of excess dibutyryl cAMP. Protein kinase C was not required for the response since short-term incubation with the phorbol esters phorbol 12 myristate, 13 acetate (PMA) and phorbol 12,13-dibutyrate (PDBu) did not mimic the 5-HT effect. Moreover, 5-HT increased Na+/K+ ATPase activity after inactivation of protein kinase C by overnight incubation with PMA. 5-HT and the sesquiterpene lactone thapsigargin increased cytosolic calcium in this cell model, and the EC50 for 5-HT corresponded with that for stimulation of Na+/K+ ATPase. Both thapsigargin and A23187, a calcium ionophore, also increased Na+/K+ ATPase activity in a dose-responsive fashion. The response to 5-HT, thapsigargin, and A23187 was blocked by conditions that removed the cytosolic calcium response. By two-dimensional gel electrophoresis, we established evidence for a calcium-sensitive but protein kinase C-independent signaling pathway. We conclude that the 5-HT1A receptor, which we have previously shown to stimulate phosphate uptake via protein kinase C, stimulates Na+/K+ ATPase via a calcium-dependent mechanism. This provides evidence for regulation of two separate transport processes by a single receptor subtype via different signaling mechanisms.
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PMID:Short-term regulation of Na+/K+ adenosine triphosphatase by recombinant human serotonin 5-HT1A receptor expressed in HeLa cells. 217 7

Administration of serotonin (5-hydroxytryptamine, 5-HT) to pyramidal cells of the CA1 region of the hippocampus results in a hyperpolarizing response which is followed by a rebound depolarization and a decrease in the calcium-activated afterhyperpolarization (AHP). While the hyperpolarizing response has been previously shown to be mediated by receptors of the 5-HT1A subtype, the identity of the receptor(s) involved in the depolarizing response and decrease of the AHP have not been identified. In the present study the effectiveness of a series of 5-HT receptor antagonists in blocking the membrane depolarization and reduction of the AHP was assessed. While a variety of 5-HT1 and 5-HT2 antagonists were found to be ineffective, the substituted benzamide BRL 24924 was found to be a potent and selective antagonist of the 5-HT-induced depolarization and decrease in the AHP in this region. This effect however appeared unrelated to the ability of this compound to block 5-HT3 receptors, as ICS 205-930 and MDL 72222 were markedly less efficacious in blocking these effects of 5-HT. Upon blockade of 5-HT1A receptors, 5-HT elicits a depolarization which is accompanied by a marked increase in excitability. These effects were also dose-dependently antagonized by BRL 24924. The present results thus suggest the presence in the CA1 region of the hippocampus of a novel 5-HT receptor at which BRL 24924 functions as a selective antagonist and which is capable of mediating slow excitatory responses in central neurons.
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PMID:Pharmacological and functional analysis of a novel serotonin receptor in the rat hippocampus. 222 19

The effect of 5-hydroxytryptamine (5-HT) receptor stimulation on protein kinase C (PKC) activity and translocation was assessed in slices or synaptosomes obtained from rat brain. Serotonin (0.5-100 microM) and the specific 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.01-10 microM) but not the 5-HT1A or 5-HT1B agonists elicited time- and dose-related translocations in cortical slices. The maximal translocation elicited by 5-HT (10-100 microM, 15 min) or DOI (1 microM, 10 min) was similar to that achievable by the phorbol ester phorbol myristate acetate (PMA) (162 nM). In synaptosomes, short exposures to depolarizing concentrations of K+ (45-65 mM) resulted in PKC translocation. In addition, PMA but not serotonin induced enzyme translocation in synaptosomes. In slices, serotonin-stimulated PKC translocation was prevented by 5-HT2 antagonists but not by dopamine or alpha-adrenergic antagonists. PKC translocation induced by serotonin but not by PMA was inhibited by incubation of slices in a Ca2+-free medium. However, addition of 0.5 mM ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid to the incubation mixture abolished the effects of both serotonin and PMA. These results indicate that, in cortical slices, serotonin operating via a 5-HT2 postsynaptic receptor can induce the translocation of PKC from cytosol to membrane. This action of the neurotransmitter appears to be dependent on extracellular Ca2+.
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PMID:Central 5-hydroxytryptamine receptor-linked protein kinase C translocation: a functional postsynaptic signal transduction system. 230 46

1 Palmitoyl carnitine, a lipid metabolite which accumulates in cytoplasmic membranes during ischaemia, has been shown to resemble the Ca2+ channel activator, Bay K 8644, in K+-depolarized smooth muscle. Palmitoyl carnitine caused concentration-dependent (1-1000 mumol l-1) augmentations in the sensitivity to Ca2+ of K+-depolarized taenia preparations from the guinea-pig caecum. The (+/-)-isomer was equieffective with the (-)-isomer, whereas carnitine was ineffective and palmitic acid relaxed the tissues. The shift to the left of Ca2+ concentration-response curves induced by palmitoyl carnitine (100 mumol l-1) was additive with that of Bay K 8644 (1 mumol l-1). 2 The interactions of palmitoyl carnitine with the different classes of calcium-antagonist were similar to those seen with Bay K 8644. Schild plots of the calcium-antagonist effects of nifedipine were shifted to the right following preincubation of the taenia with palmitoyl carnitine (30-300 mumol l-1). The inhibitory effects of verapamil were especially sensitive to palmitoyl carnitine (100 mumol l-1). Whereas the potency of diltiazem as a calcium-antagonist was reduced by palmitoyl carnitine (100 mumol l-1), the inhibitory effects of the lipophilic class III calcium-antagonists, cinnarizine and flunarizine, were entirely resistant to palmitoyl carnitine (100 mumol l-1). 3 Although palmitoyl carnitine has detergent properties in high concentrations and lyses red blood cells, these effects were not Ca2+-dependent, nor were they modified by calcium-antagonists. Other detergents did not have selective interactions with Ca2+ channels. 4 Palmitoyl carnitine inhibited [3H]-nitrendipine, [3H]-verapamil and [3H]-diltiazem binding to rat cortical membranes with IC50 values (mumol l-1) of 120 +/- 1, 95 +/- 17 and 120 +/- 15 mumol l-1 respectively. The inhibition showed little temperature-dependence, in contrast to that of Bay K 8644, except for a small reduction in the IC50 value for [3H]-verapamil binding at 37 degrees C (42 +/- 5 mumol l-1). Palmitoyl carnitine interacted selectively with the Ca2+ channel, in that effects on ligand binding to alpha-adrenoceptors, beta-adrenoceptors and 5-HT1A receptors occurred only at 5-10 fold higher concentrations. 5 It is concluded that palmitoyl carnitine, at concentrations which have previously been shown to occur in the cytoplasm during myocardial ischaemia, may interact directly with Ca2+ channels and may therefore be considered as an endogenous modulator of channel function. The site of action differs from that of other agents.
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PMID:Direct activation of Ca2+ channels by palmitoyl carnitine, a putative endogenous ligand. 244 6

Intracellular recordings were made from fetal mouse spinal cord neurons in primary culture. One type of neuron, with large somata (40-50 microns diameter) and thick neurites exhibited endogenous bursting or beating pacemaker electrical activity. Noradrenaline depolarized this type of neuron by decreasing an M-like conductance. Micropressure application of serotonin (10(-5) M in the delivery pipette) onto the surface of pacemaker neurons evoked a depolarization of the membrane potential in a dose-dependent manner with an increased input resistance. No such response was observed with other types of spinal cord neurons in culture. The response to serotonin was partially voltage-dependent. The serotonin-induced depolarization reversed at holding potential close to -100 mV. However, the input resistance variation evoked by serotonin increased exponentially when membrane potential was depolarized. The reversal potential was modified by increasing extracellular K+ concentration and it was unaltered by increasing the intracellular Cl- concentration. The decrease in K+ conductance induced by serotonin was not suppressed by the application of tetraethylammonium (50 mM) or 4-aminopyridine (10 mM). Furthermore, application of Ba2+ (6 mM) or Cd2+ (0.1 mM) had no effect on this response, suggesting that the depolarization evoked by serotonin application was not calcium-dependent. The serotonin evoked increase in input resistance was mediated by activation of a 5-HT1A-like receptor site. Spiperone, a 5-HT1A antagonist reversibly blocked the response. Methiothepin, a 5-HT1-5-HT2 antagonist (10(-3) M); cocaine, a 5-HT3 antagonist (10(-3) M); ketanserin, a 5-HT2 antagonist (10(-3) M); and prazosin, an alpha 1 antagonist (10(-3) M) had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Excitatory effect of serotonin on pacemaker neurons in spinal cord cell culture. 247 69

In vivo dialysis coupled to high-performance liquid chromatography with electrochemical detection (HPLC-EC) was used for measurement of extracellular serotonin (5-HT) in the hypothalamus of unanesthetized, unrestrained rats. A series of experiments was carried out to determine if 5-HT in the dialysis solution was released from nerve terminals. Fenfluramine, a 5-HT-releasing drug and fluoxetine, a 5-HT-reuptake inhibitor, both significantly increased extracellular 5-HT. Elevating potassium concentration in the dialysis solution also significantly increased 5-HT. Reciprocally, 5-HT was significantly reduced to about half of control levels with either local administration of tetrodotoxin, zero calcium dialysis solution, or systemic administration of 8-hydroxy-2-(di-n-propylamino)tetralin, a 5-HT1A agonist that suppresses 5-HT neuronal activity via activation of the somatodendritic autoreceptor. In addition, 5-HT levels were elevated during the dark portion of the light-dark cycle, a period when rats are more active. Changes in extracellular 5-hydroxyindoleacetic acid (5-HIAA) rarely followed changes in 5-HT. The results indicate that 5-HT in the dialysis solution, but not 5-HIAA, was a reliable measure of depolarization-induced release of 5-HT from nerve terminals. This is the first report establishing the reliability of in vivo dialysis coupled to HPLC-EC for measurement of synaptically released 5-HT.
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PMID:Extracellular serotonin and 5-hydroxyindoleacetic acid in hypothalamus of the unanesthetized rat measured by in vivo dialysis coupled to high-performance liquid chromatography with electrochemical detection: dialysate serotonin reflects neuronal release. 247 59

[3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT) is thought to label a single population of serotonin (5-HT)1A receptor, but some reports implicate multiple binding sites exist. In addition, while 5-HT1A receptor activates or inhibits adenylate cyclase, 5-HT1A receptor high and low affinity states are not reported. In this experiment, we found that [3H]8-OH-DPAT had multiple binding sites, which contained 5-HT1A receptor high and low affinity states, in rat brain membranes. [3H]8-OH-DPAT saturation binding experiment revealed high and low affinity binding sites existed. High affinity binding site was dense in hippocampus and sparse in striatum. 5-HT agonist and antagonist biphasically displaced [3H]8-OH-DPAT binding in frontocortical, hippocampal, and striatal membranes. These drugs potently displaced high affinity [3H]8-OH-DPAT binding, but clomipramine (5-HT reuptake inhibitor) potently displaced low affinity binding. High affinity [3H]8-OH-DPAT binding site was decreased by guanosine triphosphate and Na+, but increased by divalent cations, implicating coupling with G protein(s). Low affinity [3H]8-OH-DPAT binding site was decreased by cations, especially by monovalent cations and Ca2+. After the destruction of 5-HT neuron by parachloroamphetamine, only the low affinity binding site decreased. These results indicate that [3H]8-OH-DPAT not only labels the 5-HT1A receptor high and low affinity states but has presynaptic binding site relating to 5-HT reuptake site.
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PMID:[Multiple [3H]8-hydroxy-2-(di-n-propylamino)-tetralin binding sites in rat brain: modulation by GTP and cations]. 253 Jul 29

[3H]5-Methyl-urapidil, a potent antihypertensive derivative of urapidil, binds to alpha 1A-adrenoceptors in rat brain cortex membranes with a dissociation constant (KD) of 0.89 nM and a Bmax of 116 fmol/mg protein. The ligand does not bind to purified liver cell membranes (alpha 1B-adrenoceptors). [3H]5-Methyl-urapidil also labels 5-HT1A receptors in brain membranes (KD: 0.84 nM and Bmax: 235 fmol/mg protein). (+/-)-Niguldipine, a novel 1,4-dihydropyridine with Ca2+-antagonistic as well as alpha 1A-adrenoceptor blocking properties, is a competitive inhibitor of [3H]5-methyl-urapidil binding to alpha 1A-adrenoceptors. In contrast to those for prazosin, the Ki values for niguldipine were highly dependent on the membrane protein concentration, indicating partitioning of niguldipine into hydrophobic compartments unavailable for alpha-adrenoceptor interaction. The extrapolated, 'true' Ki values were as follows: (+/-)-niguldipine: 0.298 nM, (-)-niguldipine: 3.12 nM, (+)-niguldipine: 0.145 nM.
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PMID:Stereoselective binding of niguldipine enantiomers to alpha 1A-adrenoceptors labeled with [3H]5-methyl-urapidil. 255 6

1. 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and flesinoxan, agents which show high affinity and selectivity for 5-HT1A receptors, were administered intravenously in doses of 0.003 to 0.1 and 0.01 to 0.3 mg kg-1 respectively to 5 rabbits each. Their effects were compared with those of the centrally acting agent and alpha 2-adrenoceptor agonist, guanfacine, 0.01-0.3 mg kg-1, administered to a group of 5 rabbits. Five further rabbits were used as controls and treated with the vehicle of the active agents. 2. Both flesinoxan and 8-OH-DPAT induced similar systemic and regional haemodynamic changes. Both lowered mean arterial pressure and heart rate. The principal blood pressure lowering mechanism was vasodilatation; cardiac output changed minimally despite the falls in heart rate and myocardial contractile force. 3. With guanfacine the maximal fall of blood pressure was comparable to that obtained with the 5-HT1A receptor ligands; however, in contrast to the latter, the dose-response curve was U-shaped, the highest dose eliciting a pressor effect with reversal of the vasodilatation. 4. Widespread peripheral vasodilatation was found with all the agents in the splanchnic circulation and also in the brain and skeletal muscle. A weak tendency towards vasodilatation was found in the kidneys where the dose-response curve was bell-shaped for guanfacine. 5. This spectrum of activity is different from that of peripheral vasodilators, such as calcium antagonists, potassium channel activating agents or hydralazine; it is, however, consistent with the putative mechanism of action of these compounds to reduce peripheral sympathetic tone by a central mechanism of action.
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PMID:8-OH-DPAT, flesinoxan and guanfacine: systemic and regional haemodynamic effects of centrally acting antihypertensive agents in anaesthetized rabbits. 256 44


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