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 action of 5-hydroxytryptamine (5-HT) via the 5-HT1A receptor on dissociated rat dorsal raphe neurons was characterized under the whole-cell mode by using the nystatin-perforated patch-clamp technique. Under voltage-clamp conditions, 5-HT induced an inwardly rectifying K+ current (I5-HT) in a concentration-dependent manner. I5-HT was mimicked by 8-OH-DPAT and buspirone, which are both 5-HT1A receptor agonists. I5-HT was reversibly blocked by such 5-HT1A receptor antagonists as (S)-UH-301 a 5-HT4 receptor antagonist. I5-HT was antagonized concentration-dependently by such K+ channel blockers as quinine, Ba2+ and 4-aminopyridine but was relatively insensitive to both CS+ and tetraethylammonium. When the neurons were loaded with guanosine 5'-O-3-thiotriphosphate through a patch pipette, the K+ current induced by 5-HT became irreversible. N-ethylmaleimide (NEM), a sulfhydryl alkylating agent, irreversibly blocked I5-HT. The intracellular perfusion with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), a Ca2+ chelator, or neomycine, a phospholipase C inhibitor, never significantly affected the 5-HT-induced response. 12-Myristate 13-acetate diester (PMA), a protein kinase C (PKC) activator, had only a weak inhibitory effect on I5-HT, and staurosporine, a PKC inhibitor, failed to significantly occlude I5-HT. Therefore, the K+ conductance activated via the 5-HT1a receptor of dorsal raphe neurons was thus characterized by the sensitivity to such K+ channel blockers as quinine, Ba2+ and 4-aminopyridine. Moreover, G protein which is NEM-sensitive and can couple to the 5-HT1A receptor, is thus considered to activate the inwardly rectifying K+ conductance without being mediated by such second messengers as Ca2+ and PKC.
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PMID:Characterization of the K+ current mediated by 5-HT1A receptor in the acutely dissociated rat dorsal raphe neurons. 903 20

The ligand binding characteristics of the recombinant human 5-HT1A receptor stably expressed in a Chinese Hamster Ovary (CHO) cell line are described using a selective agonist, [3H]8-OH-DPAT, and a novel antagonist radioligand, [3H]WAY-100635. The association of [3H]WAY-100635 was a time- and temperature-dependent process. Mn2+ > Ca2+ > Mg2+ reduced the specific [3H]WAY-100635 binding in a concentration-dependent manner, whereas Na+ and K+ were ineffective. Scatchard analyses revealed a homogeneous population of [3H]WAY-100635 recognition sites (Kd = 0.32 nM; Bmax = 162 fmol/mg of protein). Addition of divalent cations to the incubation medium produced a two-fold decrease in the binding affinity of [3H]WAY-100635 with no significant change in Bmax; GTP gamma S had no effect on Kd or Bmax parameters. [3H]WAY-100635 displayed a higher affinity (2-3 fold) for the 5-HT1A site when compared with [3H] 8-OH-DPAT binding under similar incubation conditions. Furthermore, [3H] 8-OH-DPAT labelled approximately 53-61% of total 5-HT1A sites recognised by [3H]WAY-100635. The competition binding profiles of [3H]WAY-100635 and [3H]8-OH-DPAT were highly correlated and consistent with the recognition of 5-HT1A receptors. Agonist competition curves with [3H]WAY-100635 were best-resolved into high- and low-affinity binding states, whereas partial agonist and antagonist curves were best-fit to one-site binding models. A significant correlation between the respective affinities of a range of agonists and antagonists at recombinant human and rodent hippocampal 5-HT1A binding sites (previously published) was also observed using [3H]WAY-100635 (r = 0.92; P < 0.0005) and [3H]8-OH-DPAT (r = 0.96; P < 0.0005). The availability of a novel, high-affinity antagonist radioligand, [3H]WAY-100635, will provide a useful tool for the further characterisation of 5-HT1A receptor pharmacology.
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PMID:Pharmacological characterization of recombinant human 5-hydroxytryptamine1A receptors using a novel antagonist radioligand, [3H]WAY-100635. 904 68

The effect of serotonin (5-hydroxytryptamine, 5-HT) on Ca2+ mobilization in bovine adrenal chromaffin cells in culture was examined. 5-HT (10(-5) M) did not increase secretion of catecholamine, uptake of 45Ca2+ and levels of intracellular free Ca2+ ([Ca/+]i). However, 5-HT (10(-8)-10(-5) M) stimulated the efflux of 45Ca2+ from cultured bovine adrenal chromaffin cells in a concentration-dependent manner. Its stimulatory effect on 45Ca2+ efflux was inhibited by cyproheptadine (a 5-HT1A and 5-HT2 receptor antagonist) or mianserin (a 5-HT2 receptor antagonist). The increase in 5-HT-stimulated 45Ca2+ efflux was dependent on extracellular Na+ concentration, but not extracellular Ca2+ concentration. These results indicate that stimulation of the 5-HT receptors induces extracellular Na(+)-dependent Ca2+ efflux from bovine adrenal chromaffin cells in culture, probably by acceleration of Na+/Ca2+ exchange.
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PMID:Serotonin increases Na(+)-dependent Ca2+ efflux from bovine adrenal chromaffin cells in culture. 905 12

5-HT1A receptors couple to many signaling pathways in CHO-K1 cells through pertussis toxin-sensitive G proteins. The purpose of this study was to determine which members of the Gi/o/z family mediate 5-HT1A receptor-activated Na+/H+ exchange as measured by microphysiometry of cell monolayers. The method was extensively validated, showing that proton efflux was sodium-dependent, inhibited by amiloride analogs, and activated by growth factors, phorbol ester, calcium ionophore, and hypertonic stress. 5-HT and the specific agonist (+/-)-8-hydroxy-2-(di-N-propylamino)tetralin hydrobromide rapidly stimulated proton efflux that was blocked by a specific receptor antagonist, amiloride analogs or pertussis toxin. The activation by 5-HT depended upon extracellular sodium and could be demonstrated under conditions of imposed intracellular acid load, as well as in the presence and absence of glycolytic substrate. Acceleration of proton efflux was not inhibited by sequestration of G protein betagamma-subunits, a maneuver that blocked 5-HT1A receptor activation of mitogen-activated protein kinase. Transfection of Gzalpha and pertussis toxin-resistant mutants of Goalpha and Gialpha1 did not reverse the blockade induced by pertussis toxin. In contrast, pertussis toxin-resistant mutants of Gialpha2 and Gialpha3 "rescued" the ability of 5-HT to increase proton efflux after pertussis toxin treatment. These experiments demonstrate clearly that Gialpha2 and Gialpha3 can specifically mediate rapid agonist-induced acceleration of Na+/H+ exchange.
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PMID:5-HT1A receptor activates Na+/H+ exchange in CHO-K1 cells through Gialpha2 and Gialpha3. 906 39

We characterized whole cell barium currents through calcium channels and investigated the effects of serotonin (5-HT) on calcium channel currents and firing behavior in visualized caudal raphe neurons of the neonatal rat in brain stem slices (n = 201). A subpopulation of recorded neurons was recovered after staining for tryptophan hydroxylase (TPH), the 5-HT synthesizing enzyme (n = 21); of those cells, 86% were TPH immunoreactive, suggesting that the majority of recorded neurons was serotonergic. Calcium channel currents began to activate at about -40 mV in caudal raphe neurons and showed a peak amplitude of 952.2 +/- 144.2 (SE) pA at -10 mV. A small low-voltage activated current was also observed (approximately 22 pA). Calcium channel currents were potently inhibited by bath-applied 5-HT in most cells tested (approximately 90%). The EC50 for inhibition of calcium current by 5-HT was 0.1 microM; a saturating concentration (1.0 microM) blocked approximately 40% of the current evoked at 0 mV from a holding potential of -70 mV (n = 101). Current inhibition was associated with a slowing of activation kinetics and a shift in the peak of the current-voltage relationship, and was partially relieved by strong depolarizations. Current inhibition by 5-HT was mimicked by 8-OH-DPAT, a specific 5-HT1A agonist, and blocked by the 5-HT1a antagonists NAN 190 and (+) WAY 100135, but was unaffected by ketanserin, a 5-HT2A/C antagonist. omega-Conotoxin GVIA (omega-CgTx)-sensitive N-type channels and omega-agatoxin IVA (omega-AgaIVA)-sensitive P/Q-type channels together accounted for most of the calcium current (36 and 37%, respectively). Nimodipine had no effect on the calcium current, indicating that caudal raphe neurons do not express dihydropyridine-sensitive L-type currents. A substantial residual current (27%) remained after application of omega-CgTx, omega-AgaIVA, and nimodipine. Most of the 5-HT-sensitive calcium current was blocked by omega-CgTx and omega-AgaIVA; 5-HT had little effect on the residual current. Inhibition of calcium current by 5-HT was irreversible when GTP gamma S, a nonhydrolyzable guanosine 5'-triphosphate (GTP) analogue, was substituted for GTP in the pipette. In addition, the effects of 5-HT were blocked by pretreating slices with pertussis toxin (PTX). Together these data indicate that inhibition of N- and P/Q-type calcium current in serotonergic caudal raphe neurons is mediated by a 5-HT1A receptor via PTX-sensitive G proteins. Under current clamp, calcium channel toxins (omega-CgTx and omega-AgaIVA) and 5-HT each caused a decrease in the spike afterhyperpolarization and enhanced the repetitive firing response to injected current. The similar effects of 5-HT and the calcium channel toxins on firing behavior suggest that those effects of 5-HT were secondary to inhibition of N- and P/Q-type calcium channels.
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PMID:Effects of serotonin on caudal raphe neurons: inhibition of N- and P/Q-type calcium channels and the afterhyperpolarization. 908 3

The modulation of high-voltage-activated (HVA) Ca2+ channels by serotonin (5-HT) was studied in ventromedial hypothalamic (VMH) neurons acutely dissociated from 12-14-day-old Wistar rats using the whole-cell and nystatin perforated-patch recording configurations. 5-HT inhibited the HVA Ca2+ channels in a concentration-, time- and voltage-dependent manner. This inhibition was mimicked by the 5-HT1A agonist 8-hydroxy-dipropylaminotetralin and was prevented by pretreatment with pertussis toxin (PTX). omega-Conotoxin-GVIA, omega-agatoxin-IVA, nicardipine and omega-conotoxin-MVIIC blocked each fraction of HVA Ca2+ channel currents, suggesting the existence of N-, P-, L- and Q-types of HVA Ca2+ channels. A component of the current resistant to these Ca2+ channel antagonists also existed in the VMH neurons. Among these five components of HVA Ca2+ channel currents, the N- and Q-type currents were significantly inhibited by 5-HT. These findings suggest that the activation of 5-HT1A receptors produces the selective inhibition of N- and Q-type Ca2+ channels through a PTX-sensitive G-protein in rat VMH neurons.
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PMID:Serotonin modulates high-voltage-activated Ca2+ channels in rat ventromedial hypothalamic neurons. 912 12

We compared the electrophysiological responses to serotonin (5-HT) of neonatal and juvenile rat hypoglossal motoneurons (HMs) by using intracellular recording techniques in a brainstem slice preparation. In neonatal HMs (</=P8), 5-HT caused a substantial decrease in the amplitude of spike afterhyperpolarization (AHP) that was associated with an increase in the minimal repetitive firing frequency (Fmin). Previous work has shown that this effect of 5-HT was mediated by the 5-HT1A receptor and may be secondary to inhibition of N- and P/Q-type calcium channels. In contrast to results from neonates, we found that 5-HT did not inhibit the AHP in juvenile HMs (>/= P20). Application of a cocktail of calcium channel toxins (omega-Conotoxin-GVIA and omega-Agatoxin-IVA) to juvenile HMs substantially inhibited the AHP, indicating that calcium entry through N- and P/Q-type channels supports the AHP in juvenile HMs, as it does in neonates. In addition, intracellular injection of the long-lasting GTP analog GTPgammaS induced an agonist-independent increase in Fmin similar to that seen in neonates in the presence of 5-HT. Together, these results suggested that intracellular mechanisms downstream of the 5-HT1A receptor capable of inhibiting the AHP were intact in juvenile HMs. Therefore, we investigated the possibility that age-related changes in effects of 5-HT on the AHP resulted from altered expression of the 5-HT1A receptor. To this end, we performed ligand-binding autoradiography using [3H]8-OH-DPAT, a 5-HT1A agonist, and in situ hybridization using radiolabeled oligonucleotide probes specific for the 5-HT1A receptor. The two approaches gave remarkably similar results. The highest levels of 5-HT1A receptor expression were found in neonatal HMs, with maximal binding and hybridization at approximately postnatal day 7 (P7) and only low levels of receptor expression by P28. Finally, immunohistochemistry for 5-HT revealed that these developmental changes in 5-HT1A receptor expression occurred coincident with a postnatal increase in serotonergic innervation of the hypoglossal nucleus (nXII). Together, these findings indicate that developmental changes occur in the serotonergic innervation of nXII and in the expression of 5-HT1A receptors in HMs during the early postnatal period, resulting in markedly different effects of 5-HT on firing behavior in neonatal and juvenile HMs.
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PMID:Postnatal development of serotonergic innervation, 5-HT1A receptor expression, and 5-HT responses in rat motoneurons. 915 64

Necturus taste buds contain two primary cell types: taste receptor cells and basal cells. Merkel-like basal cells are a subset of basal cells that form chemical synapses with taste receptor cells and with innervating nerve fibers. Although Merkel-like basal cells cannot interact directly with taste stimuli, recent studies have shown that Merkel-like basal cells contain serotonin (5-HT), which may be released onto taste receptor cells in response to taste stimulation. With the use of whole cell voltage clamp, we examined whether focal applications of 5-HT to isolated taste receptor cells affected voltage-activated calcium current (I(Ca)). Two different effects were observed. 5-HT at 100 microM increased I(Ca) in 33% of taste receptor cells, whereas it decreased I(Ca) in 67%. Both responses used a 5-HT receptor subtype with a pharmacological profile similar to that of the 5-HT1A receptor, but the potentiation and inhibition of I(Ca) by 5-HT were mediated by two different second-messenger cascades. The results indicate that functional subtypes of taste receptor cells, earlier defined only by their sensitivity to taste stimuli, may also be defined by their response to the neurotransmitter 5-HT and suggest that 5-HT released by Merkel-like basal cells could modulate taste receptor function.
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PMID:Serotonin modulates voltage-dependent calcium current in Necturus taste cells. 916 73

Serotonin stimulates inositol phosphate production and intracellular calcium mobilization in cultured rat retinal pigment epithelial (RPE) cells through interaction with 5-HT2A receptors, but decreases cAMP production in cultured human RPE cells via 5-HT1A receptors. Studies were therefore undertaken to investigate the effect of serotonin on the cAMP system in rat RPE cells. Exposure of cultured rat RPE cells to serotonin (100 microM) for 10 minutes had no effect on the basal levels of cAMP. However, a 5 minute preincubation with serotonin potentiated the production of cAMP induced by a 5 minute exposure to forskolin (5 microM), isoproterenol (1 microM) and 5'-[N-ethylcarboxamido]-adenosine (10 microM) by 133.0%, 296.8% and 651.9%, respectively. This effect of serotonin was dose-dependent on forskolin and 5'-[N-ethylcarboxamido]-adenosine with half-maximal effects close to those reported for its action on inositol phosphates production. The antagonists ketanserin, methysergide and spiperone attenuated the action of serotonin, while yohimbine and spiroxatrine were ineffectual, thus indicating that the potentiating effect was through the 5-HT1A receptor. Incubation of cultured rat RPE cells with bradykinin stimulates inositol phosphates production with half-maximal effect observed at 1 nM. Bradykinin also potentiates the action of forskolin, isoproterenol and 5'-[N-ethylcarboxamido]-adenosine on cAMP production in a dose-dependent manner with little effect on basal levels. RPE cells exposed to serotonin (500 microM) or phorbol 12-13 dibutyrate (1 microM) for 30 minutes showed translocation of protein kinase C to the membrane from the cytosol, with 53.3% and 29.4% increases in membrane activity, respectively. Forskolin- and 5'-[N-ethylcarboxamido]-adenosine-induced cAMP production was potentiated by phorbol 12-13 dibutyrate (1 microM) treatment. The effect of both serotonin and phorbol 12-13 dibutyrate on forskolin-induced cAMP production was attenuated by pretreatment of cell cultures with the protein kinase C antagonists staurosporin and calphostin C at 1 microM. Thus, the production of cAMP in cultured rat RPE cells is potentiated by 5-HT2A receptors through activation of protein kinase C. This effect is, however, not specific since bradykinin, which stimulates inositol phosphates turnover, also potentiates stimulated cAMP production.
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PMID:Protein kinase C activation by serotonin potentiates agonist-induced stimulation of cAMP production in cultured rat retinal pigment epithelial cells. 917 59

The role of 5-HT(1B/1D) receptors in modulating extracellular 5-hydroxytryptamine (5-HT) levels in the guinea pig was investigated with the non-selective 5-HT(1B/1D) receptor inverse agonist, methiothepin, and the selective 5-HT(1B/1D) receptor partial agonists, GR 127935 (n-[4-methoxy-3-(4-methyl-1-piperizinyl)phenyl]-2'-methyl-4'-(5-me thyl-1,2,4-oxadiazole-3-yl)[1,1'-biphenyl]-4-carboxamide) and GR 125743 (n-[4-methoxy-3-(4-methyl-1-piperizinyl)phenyl]-3-methyl-4-(4-pyri dinyl)benzamide). Extracellular 5-HT levels were measured using the technique of brain microdialysis, in the frontal cortex of the freely moving guinea-pig. Extracellular 5-HT was tetrodotoxin sensitive and calcium dependent, and increased when perfused with a high concentration of K+. In addition, extracellular 5-HT levels were lowered by the 5-HT(1B/1D) receptor agonist, sumatriptan, and the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin, while perfusion of the selective serotonin re-uptake inhibitor, paroxetine, increased 5-HT in a concentration-dependent manner. Perfusion of methiothepin, GR 127935 and GR 125743 into the frontal cortex caused significant but transient increases of extracellular 5-HT. However, systemic administration of methiothepin, GR 127935 and GR 125743, at 0.3 mg/kg i.p., produced significant decreases in extracellular 5-HT, to minima of 27 +/- 3%, 31 +/- 12% and 27 +/- 13% of basal, respectively. The increase of extracellular 5-HT, following 5-HT(1B/1D) receptor inverse and partial agonist perfusion into the frontal cortex, was probably a consequence of attenuation of an endogenous 5-HT tone at terminal 5-HT autoreceptors. The unexpected decrease in 5-HT levels following systemic administration may be a result of additional attenuation of endogenous 5-HT tone at cell body autoreceptors in the raphe. Such an increase in local 5-HT levels could then stimulate 5-HT1A receptors to inhibit cell firing and hence decrease 5-HT levels in the terminal regions. This was confirmed when co-administration of the 5-HT1A receptor antagonist, WAY 100635, significantly attenuated the GR 127935 decrease in 5-HT.
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PMID:The role of 5-HT(1B/1D) receptors in the modulation of 5-hydroxytryptamine levels in the frontal cortex of the conscious guinea pig. 917 51


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