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)

A variety of receptors coupled to GTP-binding regulatory proteins (G proteins) initiate signals that culminate in activation of the mitogen-activated protein kinases ERK1 and ERK2. We demonstrate here that the human 5-HT1A receptor expressed in Chinese hamster ovary cells similarly promotes activation of ERK1 and ERK2, but that the pathway used does not conform entirely to those proposed previously for G protein-coupled receptors. Activation of ERK2 by the 5-HT1A receptor-selective agonist 8-hydroxy-N,N-dipropyl-2-aminotetralin hydrobromide (8-OH-DPAT) was inhibited completely by pertussis toxin and substantially by prolonged treatment of cells with phorbol 12-myristate 13-acetate. The implied requirement for protein kinase C, however, was negated in studies with bisindolylmaleimide and Ro-31-8220, which, although completely inhibiting activation of ERK2 by phorbol ester, had no impact on activation by 8-OH-DPAT. The anticipated inhibition by the tyrosine kinase inhibitors genistein and herbimycin A, moreover, was marginal at best. As expected for a Gi-coupled receptor, the inhibitors of phosphatidylinositol 3-kinase wortmannin and LY294002 inhibited activation of ERK2, albeit only partly (70%). Of significance, an inhibitor of a phosphatidylcholine-specific phospholipase C, tricyclodecan-9-yl-xanthogenate (D609), caused a similar degree of inhibition. When the two types of inhibitors were combined, an almost complete inhibition was achieved. Our data suggest that phosphatidylinositol 3-kinase and phosphatidylcholine-specific phospholipase C represent components of different, but partly overlapping pathways that can account almost entirely for the activation of ERK2 by the 5-HT1A receptor.
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PMID:Activation of a mitogen-activated protein kinase (ERK2) by the 5-hydroxytryptamine1A receptor is sensitive not only to inhibitors of phosphatidylinositol 3-kinase, but to an inhibitor of phosphatidylcholine hydrolysis. 879 86

Serotonin (5-HT) is a potent mitogen in many cells types, an action which is frequently mediated through pertussis toxin-sensitive G proteins. In the current study, we used pharmacological inhibitors and dominant negative signaling constructs to delineate elements which participate in the activation of MAPK, a growth-associated mitogen-activated protein kinase, by human G protein-coupled 5-HT1A receptor transfected into CHO-K1 cells in a stable manner. The activation pathway does not directly involve phorbol ester-sensitive protein kinase C types, but does require (i) pertussis toxin-sensitive G protein beta gamma-subunits, (ii) a staurosporine- and genistein-sensitive protein kinase, (iii) phosphoinositide-3'-kinase activity, (iv) activation of Sos in a multimolecular complex that contains p46Shc, and p52Shc, and Grb2, (v) the GTPase p21Ras, and (vi) the protein kinase p74Raf-1. These data demonstrate that the 5-HT1A receptor mediates MAPK activity by convergence upon a common activation pathway that is shared with receptor tyrosine kinases.
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PMID:Ras-dependent activation of fibroblast mitogen-activated protein kinase by 5-HT1A receptor via a G protein beta gamma-subunit-initiated pathway. 890 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 used whole cell current- and voltage-clamp recording in neonatal rat brain stem slices to characterize firing properties and effects of serotonin (5-HT) on neurons (n = 225) in raphe pallidus (RPa) and raphe obscurus (ROb). Of a sample of 51 Lucifer yellow-filled neurons recovered after immunohistochemical processing to detect tryptophan hydroxylase (TPH), 34 were found to be TPH immunoreactive (i.e., serotonergic). Serotonergic neurons had long-duration action potentials and fired spontaneously at low frequency (approximately 1 Hz) in a pattern that was often irregular; at higher firing frequencies the discharge became more regular. These neurons displayed spike frequency adaptation, with maximal steady-state firing rates of < 4 Hz. The overwhelming majority of identified serotonergic neurons was hyperpolarized by bath-applied 5-HT (94%; n = 32 of 34); conversely, most cells in this sample that were hyperpolarized by 5-HT were serotonergic (78%; n= 32 of 41). TPH-immunonegative neurons were separated into two populations. One group had properties that were indistinguishable from those of serotonergic caudal raphe neurons. The other group was truly distinct; those neurons had more hyperpolarized resting membrane potentials, were not spontaneously active, had shorter-duration action potentials, and were depolarized by 5-HT. Caudal raphe neurons responded to 5-HT (1-5 microM) with membrane hyperpolarization in current clamp (-13.4 +/- 1.1 mV, mean +/- SE) or with outward current in voltage clamp (16.0 +/- 1.4 pA). The current induced by 5-HT was inwardly rectifying and associated with an increase in peak conductance and was highly selective for K+. It was completely blocked by 0.2 mM Ba2+ but not by glibenclamide, an inhibitor of ATP-sensitive K+ channels. Effects of 5-HT were dose dependent, with an EC50 of 0.1-0.3 microM. The 5-HT1A agonist 8-OH-DPAT mimicked, and the 5-HT1A antagonists (+)WAY 10,0135 and NAN 190 blocked, effects of 5-HT. The 5-HT2A/C antagonist ketanserin did not inhibit the effects of 5-HT. Fewer 5-HT-responsive neurons were encountered in slices exposed acutely to pertussis toxin (approximately 13%) than in adjacent control slices not exposed to pertussis toxin (approximately 85%). In addition, in neurons recorded with pipettes containing GTP gamma S (0.1 mM), 5-HT induced an inwardly rectifying current that did not reverse on washing. In many cells recorded with GTP gamma S, a current developed in the absence of agonist that had properties identical to those of the 5-HT-sensitive current; when followed for extended periods, the agonist-independent GTP gamma S-induced conductance desensitized, returning toward control levels with a time constant of approximately 18 min. Together these results indicate that serotonergic neurons of ROb and RPa are spontaneously active in a neonatal rat brain stem slice preparation and that hyperpolarization of those neurons by 5-HT1A receptor stimulation is due to pertussis toxin-sensitive G protein-mediated activation of an inwardly rectifying K+ conductance. In addition, we identified a group of nonserotonergic medullary raphe neurons that had distinct electrophysiological properties and that was depolarized by 5-HT.
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PMID:Effects of serotonin on caudal raphe neurons: activation of an inwardly rectifying potassium conductance. 908 2

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

The antinociceptive effects of the 5-HT1A agonists buspirone [3 mg/kg intraperitoneally (i.p.)], gepirone (3-6 mg/kg i.p.), and 8-OH-DPAT [3-5 mg/kg i.p.; 1-3 micrograms per mouse intracerebroventricularly (i.c.v.)] were examined in mice by using the hot-plate (thermal stimulus) and abdominal constriction (chemical stimulus) tests. Buspirone, gepirone, and 8-OH-DPAT produced significant antinociception, which was prevented by atropine (5 mg/kg i.p.), the ACh depletor hemicholinium-3 (1 microgram per mouse i.c.v.), and the 5-HT1A antagonist NAN 190 (0.5 microgram per mouse i.c.v.), but not by naloxone (1 mg/kg i.p.), the GABAB antagonist CGP 35348 (100 mg/kg i.p.), and pertussis toxin (0.25 microgram per mouse i.c.v.). NAN 190 which totally antagonized buspirone, gepirone, and 8-OH-DPAT antinociception, did not modify the analgesic effect of morphine (5 mg/kg subcutaneously). In the antinociceptive dose range, none of the 5HT1A agonists impaired mouse performance evaluated by rota-rod and hole board tests. On the basis of these data, it can be postulated that buspirone, gepirone, and 8-OH-DPAT exert an antinociceptive effect mediated by a central amplification of cholinergic transmission.
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PMID:5-HT1A agonists induce central cholinergic antinociception. 925 13

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

[35S]Guanosine-5'-O-(3-thio)triphosphate ([35S]GTPgammaS) binding to G proteins was measured by in vitro autoradiography in guinea pig and rat brain sections after activation by 5-hydroxytryptamine (5-HT) receptor agonists. 5-Carboxamidotryptamine stimulated binding strongly in hippocampus and lateral septum and weakly in substantia nigra. This effect was blocked in the substantia nigra by the 5-HT1B/1D receptor antagonist GR-127,935 and in the former two regions by the 5-HT1A antagonist NAN-190. 5-HT1B/1D receptor agonists stimulated binding in substantia nigra and in areas containing 5-HT1A receptors. In guinea pig substantia nigra, 5-(nonyloxy)-tryptamine maximally stimulated [35S]GTPgammaS binding by 54%, with an EC50 value of 62 nM; at 100 microM, this agonist increased binding by approximately 200% in hippocampus (with a 2-fold weaker EC50 value). The distribution of [3H]8-OH-DPAT binding sites was identical to that of the [35S]GTPgammaS labeling stimulated by the 5-HT1A agonist (R)-8-hydroxy-2-dipropylaminotetralin [(R)-8-OH-DPAT)]. (R)-8-OH-DPAT, (S)-8-OH-DPAT, and buspirone stimulated [35S]GTPgammaS binding in hippocampus by 340%, 140%, and 78%, with EC50 values of 71, 51, and 132 nM. Enhanced [35S]GTPgammaS binding was not detected in the presence of 5-HT1F, 5-HT2, 5-HT4, and 5-HT7 receptor agonists. Because activation of mu-opioid, muscarinic M2, histamine H3, and cannabinoid receptors was also visualized successfully, these data suggest that only receptors coupled to pertussis toxin-sensitive G proteins can be seen by [35S]GTPgammaS binding autoradiography. This study also shows that different 5-HT receptors coupled to these proteins can show a wide range of [35S]GTPgammaS binding stimulation. Although the functional significance of these variations is unclear, this technique offers advantages over receptor autoradiography because it does not require high affinity radioligands and provides a measure of agonist efficacies in various brain regions.
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PMID:5-Hydroxytryptamine1A and 5-hydroxytryptamine1B receptors stimulate [35S]guanosine-5'-O-(3-thio)triphosphate binding to rodent brain sections as visualized by in vitro autoradiography. 938 25

1. Previous studies have shown that flupirtine, a centrally acting, non-opioid analgesic agent, also exhibits neuroprotective activity in focal cerebral ischaemia in mice and reduces apoptosis induced by NMDA, gp 120 of HIV, prior protein fragment or lead acetate as well as necrosis induced by glutamate or NMDA in cell culture. To study the potential mechanism of the neuroprotective action of flupirtine, we investigated whether flupirtine is able to modulate potassium or NMDA-induced currents in rat cultured hippocampal neurones by use of the whole-cell configuration of the patch-clamp technique. 2. We demonstrated that 1 microM flupirtine activated an inwardly rectifying potassium current (K(ir)) in hippocampal neurones (deltaI=-39+/-18 pA at -130 mV; n=10). This effect was dose-dependent (EC50=0.6 microM). The reversal potential for K(ir) was in agreement with the potassium equilibrium potential predicted from the Nernst equation showing that K(ir) was predominantly carried by K+. Furthermore, the induced current was blocked completely by Ba2+ (1 mM), an effect typical for K(ir). 3. The activation of K(ir) by flupirtine was largely prevented by pretreatment of the cells with pertussis toxin (PTX) indicating the involvement of a PTX-sensitive G-protein in the transduction mechanism (deltaI=-3+/-6 pA at -130 mV; n=8). Inclusion of cyclic AMP in the intracellular solution completely abolished the activation of K(ir) (n=7). 4. The selective alpha2-adrenoceptor antagonist SKF-86466 (10 microM), the selective 5-HT1A antagonist NAN 190 as well as the selective GABA(B) antagonist 2-hydroxysaclofen (10 microM) failed to block the flupirtine effect on the inward rectifier. 5. Flupirtine (1 microM) could not change the current induced by 50 microM NMDA. 6. These results show that in cultured hippocampal neurones flupirtine activates an inwardly rectifying potassium current and that a PTX-sensitive G-protein is involved in the transduction mechanism.
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PMID:Influence of flupirtine on a G-protein coupled inwardly rectifying potassium current in hippocampal neurones. 942 Dec 79


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