RESUMEN
Attempts to mimic synaptic delivery of acetylcholine (ACh) with brief, repetitive pulses of high concentration ACh at synapses of medial habenula (MHN) and interpeduncular nucleus (IPN) neurons in vitro elicited temporally distinct facilitation and inhibition of glutamate secretion via nicotinic and muscarinic ACh receptor-mediated pathways, respectively. ACh-induced nicotinic facilitation was sustained for up to 2 hr, whereas muscarinic inhibition was transient. Prolonged exposure to nicotine inactivated nicotinic receptors selectively, thus decreasing the relative contribution of the facilitatory versus inhibitory influences of ACh. The net effect of ACh in modulating glutamatergic transmission at MHN-IPN synapses may be determined by pre-exposure to nicotine, because the drug appears to switch the balance between the facilitatory and inhibitory actions of ACh.
Asunto(s)
Acetilcolina/farmacología , Ácido Glutámico/metabolismo , Neuronas/metabolismo , Nicotina/farmacología , Transmisión Sináptica/fisiología , Adaptación Fisiológica/efectos de los fármacos , Animales , Células Cultivadas , Embrión de Pollo , Técnicas de Cocultivo , Relación Dosis-Respuesta a Droga , Ácido Glutámico/farmacología , Habénula/fisiología , Mesencéfalo/fisiología , Inhibición Neural/efectos de los fármacos , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Neuronas/citología , Agonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/farmacología , Técnicas de Placa-Clamp , Receptores Muscarínicos/metabolismo , Receptores Nicotínicos/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Transmisión Sináptica/efectos de los fármacosRESUMEN
Presynaptic nicotinic acetylcholine receptors (nAChRs) are thought to mediate some of the cognitive and behavioral effects of nicotine. The olfactory projection to the amygdala, and intra-amygdaloid projections, are limbic relays involved in behavioral reinforcement, a property influenced by nicotine. Co-cultures consisting of murine olfactory bulb (OB) explants and dispersed amygdala neurons were developed to reconstruct this pathway in vitro. Whole cell patch-clamp recordings were obtained from amygdala neurons contacted by OB explant neurites, and spontaneous and evoked synaptic currents were characterized. The majority of the 108 innervated amygdala neurons exhibited glutamatergic spontaneous postsynaptic currents (PSCs), 20% exhibited GABAergic spontaneous PSCs, and 17% exhibited both. Direct extracellular stimulation of OB explants elicited glutamatergic synaptic currents in amygdala neurons. Antibodies to nAChR subunits co-localized with an antibody to synapsin I, a presynaptic marker, along OB explant processes, consistent with the targeting of nAChR protein to presynaptic sites of the mitral cell projections. Hence, we examined the role of presynaptic nAChRs in modulating synaptic transmission in the OB-amygdala co-cultures. Focal application of 500 nM to 1 microM nicotine for 5-60 s markedly increased the frequency of spontaneous PSCs, without a change in the amplitude, in 39% of neurons that exhibited glutamatergic spontaneous PSCs (average peak fold increase = 125.2 +/- 33.3). Nicotine also enhanced evoked glutamatergic currents elicited by direct stimulation of OB explant fibers. Nicotine increased the frequency of spontaneous PSCs, without a change in the amplitude, in 35% of neurons that exhibited GABAergic spontaneous PSCs (average peak fold increase = 63.9 +/- 34.3). Thus activation of presynaptic nAChRs can modulate glutamatergic as well as GABAergic synaptic transmission in the amygdala. These results suggest that behaviors mediated by olfactory projections may be modulated by presynaptic nAChRs in the amygdala, where integration of olfactory and pheromonal input is thought to occur.
Asunto(s)
Amígdala del Cerebelo/fisiología , Ácido Glutámico/fisiología , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Transmisión Sináptica/efectos de los fármacos , Ácido gamma-Aminobutírico/fisiología , 2-Amino-5-fosfonovalerato/farmacología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Amígdala del Cerebelo/citología , Animales , Bicuculina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Feto/fisiología , Antagonistas del GABA/farmacología , Técnicas In Vitro , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Ratones , Ratones Endogámicos C57BL , Neuronas/fisiología , Bulbo Olfatorio/citología , Bulbo Olfatorio/fisiología , Embarazo , Transmisión Sináptica/fisiologíaRESUMEN
The diversity of neuronal nicotinic acetylcholine receptors (nAChRs) is likely an important factor in the modulation of synaptic transmission by acetylcholine and nicotine. We have tested whether postsynaptic nAChRs are modulated in a subtype-specific manner by prostaglandin E(2) (PGE(2)), a regulator of neuronal excitability in both the central and peripheral nervous systems, and examined the effects of PGE(2) on nicotinic transmission. Somatodendritic nAChRs in chick lumbar sympathetic ganglia include four nAChR subtypes distinguished on the basis of conductance and kinetic profile. Nanomolar PGE(2) applied to the extrapatch membrane differentially regulates opening probability (Po), frequency and the opening duration of each nAChR channel subtype in cell-attached patches. PGE(2) decreases the Po of the predominant nAChR subtype (36 pS) and significantly increases Po and open duration of the 23 pS subtype. The 23 pS subtype is gated by the alpha 7-selective agonist choline, and choline-gated currents are inhibited by alpha-bungarotoxin. To examine whether PGE(2) modulates nAChRs at synaptic sites, we studied the effects of PGE(2) on amplitude and decay of synaptic currents in visceral motoneuron-sympathetic neuron co-cultures. PGE(2) significantly decreases the amplitude of miniature excitatory postsynaptic currents (mEPSCs), consistent with the predominant inhibition by PGE(2) of all but the 23 pS subtype. The time constant of mEPSCs at PGE(2)-treated synapses is prolonged, which is also consistent with an increased contribution of the longer open duration of the 23 pS nAChR subtype with PGE(2) treatment. To examine the presynaptic effect of PGE(2), nanomolar nicotine was used. Nicotine induces facilitation of synaptic transmission by increasing mEPSC frequency, an action thought to involve presynaptic, alpha 7-containing nAChRs. In the presence of PGE(2), nicotine-induced synaptic facilitation persists. Thus the net effect of PGE(2) is to alter the profile of nAChRs contributing to synaptic transmission from larger conductance, briefer opening channels to smaller conductance, longer opening events. This subtype-specific modulation of nAChRs by PGE(2) may provide a mechanism for selective activation and suppression of synaptic pathways mediated by different nAChR subtype(s) at both pre- and postsynaptic sites.
Asunto(s)
Dinoprostona/farmacología , Ganglios Simpáticos/citología , Neuronas/fisiología , Receptores Nicotínicos/metabolismo , Transmisión Sináptica/efectos de los fármacos , Animales , Bungarotoxinas/farmacología , Células Cultivadas , Embrión de Pollo , Colina/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Activación del Canal Iónico/efectos de los fármacos , Activación del Canal Iónico/fisiología , Plasticidad Neuronal/fisiología , Neuronas/citología , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Nootrópicos/farmacología , Médula Espinal/citología , Transmisión Sináptica/fisiología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
The profiles of presynaptic facilitation of glutamate release as elicited by nicotine and acetylcholine were compared in two limbic pathways recapitulated in vitro. At synapses of medial habenula (MHN) and interpeduncular nucleus (IPN) neurons, application of nicotine increased the frequency of TTX-resistant, spontaneous postsynaptic currents (SSCs) by an average of 5-fold. In contrast, the average increase in SSC frequency elicited by nicotine was more than 120 fold at synapses of olfactory bulb (OB) and amygdala neurons. At both preparations, pulses of ACh caused presynaptic facilitation that lasted longer than that elicited by nicotine. The subunit composition of presynaptic nAChRs may contribute to the different profiles of facilitation observed. The large magnitude, fast kinetics, and alpha-bungarotoxin sensitivity of facilitation observed at OB-amygdala synapses is consistent with participation of alpha7-type nAChRs. As subunit-selective deletion of alpha5 or alpha7 altered the profile of nicotine-elicited facilitation at MHN-IPN synapses, presynaptic nAChRs at MHN-IPN synapses appear to be more complex. Such heteromeric combinations of nAChRs may contribute to the lower magnitude and slower kinetics of presynaptic facilitation at MHN-IPN synapses. Calcium influx through either voltage-gated calcium channels or directly through presynaptic alpha7-containing nAChRs is sufficient to support nicotine-elicited facilitation of glutamate release. Resultant increases in intracellular calcium may further modulate presynaptic nAChR activity in a subunit-composition dependent manner.
Asunto(s)
Ácido Glutámico/fisiología , Receptores Nicotínicos/fisiología , Receptores Presinapticos/fisiología , Transmisión Sináptica/fisiología , Animales , Calcio/metabolismo , Embrión de Pollo , Electrofisiología , Femenino , Habénula/metabolismo , Habénula/fisiología , Mesencéfalo/metabolismo , Mesencéfalo/fisiología , Ratones , Bulbo Olfatorio/metabolismo , Bulbo Olfatorio/fisiología , Oligonucleótidos Antisentido/farmacología , Embarazo , Receptores Nicotínicos/metabolismo , Sinapsis/metabolismo , Sinapsis/fisiología , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
Neuregulin-1 (NRG-1) signaling has been implicated in inductive interactions between pre- and postsynaptic partners during synaptogenesis. We used gene targeting to selectively disrupt cysteine-rich domain-(CRD-) containing NRG-1 isoforms. In CRD-NRG-1-/-mice, peripheral projections defasciculated and displayed aberrant branching patterns within their targets. Motor nerve terminals were transiently associated with broad bands of postsynaptic ACh receptor (AChR) clusters. Initially, Schwann cell precursors accompanied peripheral projections, but later, Schwann cells were absent from axons in the periphery. Following initial stages of synapse formation, sensory and motor nerves withdrew and degenerated. Our data demonstrate the essential role of CRD-NRG-1-mediated signaling for coordinating nerve, target, and Schwann cell interactions in the normal maintenance of peripheral synapses, and ultimately in the survival of CRD-NRG-1-expressing neurons.
Asunto(s)
Neuronas Motoras/fisiología , Neurregulina-1/química , Neuronas Aferentes/fisiología , Transducción de Señal/fisiología , Sinapsis/química , Animales , Comunicación Celular/fisiología , Supervivencia Celular/fisiología , Cisteína/química , Femenino , Regulación del Desarrollo de la Expresión Génica , Isomerismo , Pulmón/inervación , Pulmón/fisiología , Masculino , Ratones , Ratones Noqueados , Neuronas Motoras/química , Neuronas Motoras/citología , Músculo Esquelético/inervación , Músculo Esquelético/fisiología , Mutagénesis/fisiología , Degeneración Nerviosa/genética , Degeneración Nerviosa/fisiopatología , Neurregulina-1/genética , Neurregulina-1/metabolismo , Neuroglía/citología , Neuroglía/fisiología , Neuronas Aferentes/química , Neuronas Aferentes/citología , Nervio Frénico/química , Nervio Frénico/citología , Nervio Frénico/inmunología , Proteínas Recombinantes/genética , Mecánica Respiratoria , Rombencéfalo/embriología , Rombencéfalo/patología , Células de Schwann/citología , Células de Schwann/fisiología , Sinapsis/fisiología , Transcripción Genética/fisiologíaRESUMEN
Basic-helix-loop-helix transcription factors regulate neurogenesis and neuronal differentiation by as yet unknown mechanisms. We show that an embryonic neuronal-specific basic-helix-loop-helix protein, HEN1 (also known as NSCL1 or NHLH), interacts with 'LIM only' proteins. Examination of the expression patterns of XHEN1 and XLMO-3, the Xenopus homologues of these human genes, reveals extensive overlap during early neurogenesis: at the onset of gastrulation on the dorsal side of the blastopore lip and, subsequently, in the prospective neural plate. Binding of XLMO-3 increases the transcriptional activity of XHEN1 in vivo. Co-expression of these two genes in Xenopus embryos induces a cascade of expression of neuronal-specific basic-helix-loop-helix proteins that leads to neuronal differentiation. We propose that XHEN1, in concert with XLMO-3, is a critical regulator of neurogenesis.
Asunto(s)
Proteínas de Unión al ADN/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Factores de Transcripción/metabolismo , Secuencia de Aminoácidos , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Diferenciación Celular , Clonación Molecular , Proteínas de Unión al ADN/metabolismo , Regulación del Desarrollo de la Expresión Génica , Secuencias Hélice-Asa-Hélice , Humanos , Inmunohistoquímica , Hibridación in Situ , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/genética , Alineación de Secuencia , Tubulina (Proteína)/genética , Xenopus/embriología , Levaduras/genéticaRESUMEN
Transcripts for the beta2 and the beta4 nicotinic acetylcholine receptor (nAChR) subunits are found throughout the CNS and the peripheral nervous system. These two beta subunits can form heteromultimeric channels with any of the alpha2, alpha3, alpha4, or alpha5 subunits in heterologous expression systems. Nonetheless, the subunit composition of native nAChRs and the role of different nAChR subtypes in vivo remain unclear. We prepared null mutations for the beta2 and the beta4 genes and bred beta2-/-beta4-/- mice by mating mice of identical beta2-/-beta4+/- or beta2+/-beta4-/- genotype. The beta2-/- and the beta4-/- single-mutant mice grow to adulthood with no visible phenotypic abnormalities. The beta2-/-beta4-/- double mutants survive to birth but have impaired growth and increased perinatal mortality. They also present enlarged bladders with dribbling urination and develop urinary infection and bladder stones. The ocular pupils are widely dilated and do not constrict in response to light. Histological studies revealed no significant abnormalities of brain or peripheral tissues except for hyperplasia in the bladder mucosa of beta4-/- and beta2-/-beta4-/- mutants. Bladder strips from beta2-/-beta4-/- mice did not respond to nicotine but contracted when stimulated with a muscarinic agonist or electric field stimulation. Bladder strips from beta4 mutants did not respond to nicotine despite the absence of major bladder dysfunction in vivo. Acetylcholine-activated whole-cell currents were absent in superior cervical ganglion neurons from beta2-/-beta4-/- mice and reduced in neurons from beta4-/- mice. Although there is apparent redundancy and a superficially normal phenotype in beta2-/- and beta4-/- mice, physiological studies indicate major deficits in the beta4-/- mice. Our previous description of a similar phenotype in alpha3-/- mice and the current data suggest that the alpha3 and the beta4 subunits are major components in autonomic nAChRs. The phenotype of the beta2-/-beta4-/- and alpha3-/- mice resembles the autosomal recessive megacystis-microcolon-hypoperistalsis syndrome in humans.
Asunto(s)
Enfermedades del Sistema Nervioso Autónomo/genética , Neuronas/fisiología , Receptores Nicotínicos/fisiología , Ganglio Cervical Superior/fisiopatología , Animales , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Células Cultivadas , Cruzamientos Genéticos , Exones , Anomalías del Ojo/genética , Anomalías del Ojo/patología , Femenino , Biblioteca Genómica , Intrones , Sustancias Macromoleculares , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Noqueados , Membrana Mucosa/anomalías , Membrana Mucosa/patología , Neuronas/efectos de los fármacos , Nicotina/farmacología , Receptores Nicotínicos/deficiencia , Receptores Nicotínicos/genética , Ganglio Cervical Superior/fisiología , Vejiga Urinaria/anomalías , Vejiga Urinaria/patologíaRESUMEN
Neuronal differentiation and development of synaptic specializations are strongly influenced by cellular interactions. We compared the effects of interaction with distinct autonomic targets on the molecular and biophysical differentiation of 'upstream' neuron-neuron synapses. Contact with cardiac tissue induced expression of nicotinic receptor channels (nAChRs) distinct from those induced by renal tissue in presynaptic autonomic neurons. The kinetics of cholinergic currents at interneuronal synapses are dictated by the peripheral target contacted. Analysis of the nAChR channel subtypes and subunits in individual neurons demonstrated that the profile of transmitter receptors expressed at mature neuron-neuron synapses develops from the convergent influences of input-derived (anterograde) and target-specific (retrograde) signals.
Asunto(s)
Comunicación Celular/fisiología , Embrión de Pollo/fisiología , Neuronas/fisiología , Receptores Nicotínicos/metabolismo , Sinapsis/metabolismo , Animales , Células Cultivadas , Embrión de Pollo/citología , Embrión de Pollo/metabolismo , Conductividad Eléctrica , Corazón/embriología , Canales Iónicos/metabolismo , Riñón/embriología , Cinética , Receptores Colinérgicos/fisiología , Sistema Nervioso Simpático/embriología , Sinapsis/fisiologíaRESUMEN
Elapid snake venom neurotoxins exert their effects through high-affinity interactions with specific neurotransmitter receptors. A novel murine gene, lynx1, is highly expressed in the brain and contains the cysteine-rich motif characteristic of this class of neurotoxins. Primary sequence and gene structure analyses reveal an evolutionary relationship between lynx1 and the Ly-6/neurotoxin gene family. lynx1 is expressed in large projection neurons in the hippocampus, cortex, and cerebellum. In cerebellar neurons, lynx1 protein is localized to a specific subdomain including the soma and proximal dendrites. lynx1 binding to brain sections correlates with the distribution of nAChRs, and application of lynx1 to Xenopus oocytes expressing nAChRs results in an increase in acetylcholine-evoked macroscopic currents. These results identify lynx1 as a novel protein modulator for nAChRs in vitro, which could have important implications in the regulation of cholinergic function in vivo.
Asunto(s)
Sistema Nervioso Central/metabolismo , Glicoproteínas de Membrana/fisiología , Neuropéptidos/fisiología , Receptores Nicotínicos/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Secuencia de Aminoácidos/genética , Animales , Bungarotoxinas/genética , Sistema Nervioso Central/citología , Femenino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones , Datos de Secuencia Molecular , Familia de Multigenes/genética , Neuronas/metabolismo , Neuropéptidos/genética , Neuropéptidos/metabolismo , Oocitos , XenopusRESUMEN
The quantity of neurotransmitter released into the synaptic cleft, the reliability with which it is released, and the response of the postsynaptic cell to that transmitter all contribute to the strength of a synaptic connection. The presynaptic nerve terminal is a major regulatory site for activity-dependent changes in synaptic function. Ionotropic receptors for the inhibitory amino acid GABA, expressed on the presynaptic terminals of crustacean motor axons and vertebrate sensory neurons, were the first well-defined mechanism for the heterosynaptic transmitter-mediated regulation of transmitter release. Recently, presynaptic ionotropic receptors for a large range of transmitters have been found to be widespread throughout the central and peripheral nervous systems. In this review, we first consider some general theoretical issues regarding whether and how presynaptic ionotropic receptors are important regulators of presynaptic function. We consider the criteria that should be met to identify a presynaptic ionotropic receptor and its regulatory function and review several examples of presynaptic receptors that meet at least some of those criteria. We summarize the classic studies of presynaptic inhibition mediated by GABA-gated Cl channels and then focus on presynaptic nicotinic ACh receptors and presynaptic glutamate receptors. Finally, we briefly discuss evidence for other types of presynaptic ionotropic receptors.
Asunto(s)
Neurotransmisores/metabolismo , Terminales Presinápticos/metabolismo , Receptores de Superficie Celular/fisiología , Acetilcolina/fisiología , Animales , Humanos , Activación del Canal Iónico/fisiología , Canales Iónicos/fisiología , Inhibición Neural/fisiología , Receptores de Superficie Celular/metabolismo , Receptores de GABA-A/fisiología , Receptores de Glutamato/fisiologíaRESUMEN
1. Many studies of the alpha7 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) family have demonstrated that this alpha-bungarotoxin (alpha-BgTx)-binding neuronal receptor can participate in ACh-gated channels. Heterologous expression studies reveal that alpha7 subunits form homomeric channels of unusually high Ca2+ permeability. However, the physiological role of the alpha7 subunit in native neuronal nAChR channels is less clear. 2. We present evidence that the alpha7 subunit contributes to the function of at least three subtypes of native nAChR expressed by embryonic chick sympathetic neurones. These subtypes are functionally distinct from heterologously expressed homomeric alpha7 nAChRs as well as homomeric-like currents described in studies of hippocampal and parasympathetic neurones. 3. The proposed nAChRs differ from one another and from homomeric alpha7 nAChRs in their sensitivity to block by alpha7 subunit-specific antagonists: alpha-BgTx and methyllycaconitine (MLA). While MLA blocks 60 % of the macroscopic ACh response, alpha-BgTx inhibits a small component of the macroscopic current described by slow-on and slow-off kinetics. 4. Functional deletion of the alpha7 subunit by antisense oligonucleotide treatment eliminates the susceptibility of the nAChRs to block by both MLA and alpha-BgTx. 5. Single channel recordings combined with pharmacological and antisense-mediated 'deletion' techniques reveal that alpha-BgTx-sensitive alpha7-containing nAChRs have a small unitary conductance (18 pS), brief open time kinetics and relatively low open probability (Po). MLA-sensitive alpha7 nAChRs are characterized by a conductance of approximately 35 pS, intermediate burst duration, and a relatively high Po. 6. The third nAChR subtype deleted by alpha7 antisense treatment is characterized by a unitary conductance of 50 pS and prolonged opening duration. 7. We propose that these three populations of native alpha7-containing nAChRs are distinct heteromeric complexes that include other alpha and/or beta nAChR subunits.
Asunto(s)
Ganglios Simpáticos/citología , Activación del Canal Iónico/fisiología , Neuronas/química , Receptores Nicotínicos/genética , Acetilcolina/farmacología , Aconitina/análogos & derivados , Aconitina/farmacología , Animales , Elementos sin Sentido (Genética) , Bungarotoxinas/farmacología , Calcio/farmacología , Embrión de Pollo , Cloruros/farmacocinética , Relación Dosis-Respuesta a Droga , Conductividad Eléctrica , Eliminación de Gen , Insecticidas/farmacología , Activación del Canal Iónico/efectos de los fármacos , Cinética , Mutagénesis/fisiología , Neuronas/fisiología , Técnicas de Placa-Clamp , Receptores Nicotínicos/química , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
1. Heterologous expression studies of the alpha5 subunit of the neuronal acetylcholine receptor (nAChR) gene family have demonstrated that it can participate in the function of ACh-gated channels if co-expressed with another alpha- and a beta-subunit. Previous studies also indicate prominent expression of alpha5 in both central and peripheral nervous systems. The participation of alpha5 in native nAChRs and its functional role in these channels is, however, unknown. 2. In this study, we present evidence that alpha5 has a role in at least two distinct subtypes of nAChR complexes expressed by embryonic chick sympathetic neurones. 3. alpha5 contributes not only to agonist but also to antagonist sensitivity of natively expressed nAChR channels. Functional deletion of the alpha5 subunit by antisense oligonucleotide treatment removes the nAChRs with relatively low affinity to ACh and cytisine. Deletion of alpha5 also eliminates channels that are blocked by the alpha7-specific antagonist methyllycaconitine (MLA) while increasing the percentage of current carried by nAChRs that are sensitive to alpha-bungarotoxin (alpha-BgTx). 4. Single channel analyses indicate that functional deletion of alpha5 results in the deletion of both the 'brief' and 'long' open duration, 50 pS subtypes of nAChR channels while increasing the expression of the 18 pS, alpha-BgTx-sensitive native nAChRs normally detected in sympathetic neurones at later developmental stages. 5. The biophysical and pharmacological profiles of native nAChRs revealed by this study and previous work are discussed in the context of a proposed model of the nAChR channels expressed by chick sympathetic neurones throughout development.
Asunto(s)
Activación del Canal Iónico/fisiología , Neuronas/química , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Acetilcolina/farmacología , Aconitina/análogos & derivados , Aconitina/farmacología , Alcaloides/farmacología , Animales , Elementos sin Sentido (Genética) , Azocinas , Bungarotoxinas/farmacología , Embrión de Pollo , Relación Dosis-Respuesta a Droga , Electrofisiología , Ganglios Simpáticos/citología , Eliminación de Gen , Insecticidas/farmacología , Activación del Canal Iónico/efectos de los fármacos , Mutagénesis/fisiología , Neuronas/fisiología , Agonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/farmacología , Quinolizinas , Receptores Nicotínicos/químicaRESUMEN
The effects of prostaglandin E2 (PGE2), an important metabolite of arachidonic acid, were studied on the activity of nicotinic AChR channels in cultured chick sympathetic ganglion neurons. In whole cell recordings, PGE2 (25 nM) inhibited significantly the ACh-evoked macroscopic current. In cell-attached patch recordings, PGE2 significantly inhibited single AChR channel currents as a result of a decrease in the frequency of channel opening, with no change in open time and conductance. PGE2 did not alter the extent or rate of agonist-induced desensitization of the AChR channels. These effects are specific since the related compound PGD2 had no effect on AChR channel function. Because there is an abundant endogenous production of PGE2 within sympathetic ganglia in response to certain stimuli, the inhibition of AChR channel function by PGE2 could serve an important role to modulate synaptic transmission in the sympathetic nervous system.
Asunto(s)
Dinoprostona/farmacología , Ganglios Simpáticos/citología , Neuronas/efectos de los fármacos , Receptores Nicotínicos/efectos de los fármacos , Animales , Calcio/fisiología , Embrión de Pollo , Inhibidores de la Ciclooxigenasa/farmacología , Ganglios Simpáticos/fisiología , Indometacina/farmacología , Activación del Canal Iónico/efectos de los fármacos , Neuronas/fisiología , Norepinefrina/farmacología , Técnicas de Placa-Clamp , Prostaglandina D2/farmacología , Receptores Nicotínicos/fisiología , Transmisión SinápticaRESUMEN
1. General anesthetics have been shown to inhibit synaptic transmission in multiple areas of the central and peripheral nervous systems. 2. The mechanism of inhibition is not well understood. 3. It has become clear that general anesthetics modulate the function of members of the ligand gated ion channel superfamily, including receptors for GABA(A), glycine (Harrison et al., Mol. Pharmacol. 44(3), 1993, 628-632) and 5HT3 (Zhou and Lovinger, J. Pharmacol. Exp. Therap. 278(2), 1996, 732-740). 4. Studies of the activity of general anesthetics on recombinant neuronal nicotinic acetylcholine receptors have added this receptor family to those potently inhibited by general anesthetics (Flood et al., Anesthesiology 86(4), 1997, 859-865; Violet et al., Anesthesiology 86(4), 1997, 866-874). 5. Studies of neuronal nicotinic receptors in native neurons suggest that the inhibition of these receptors by general anesthetics at low clinical concentrations may be biologically significant (Nicoll, Science 199(4327), 1978, 451-452). 6. Recent work on neuronal nicotinic acetylcholine receptors in the central nervous system suggests that their primary role may be to modulate synaptic transmission (Role and Berg, Neuron 16(6), 1996, 1077-1085). 7. Thus, inhibition of nicotinic modulation in the central nervous system may result in inhibition of synaptic transmission and some of the behavioral consequences of general anesthesia.
Asunto(s)
Anestésicos Generales/farmacología , Neuronas/efectos de los fármacos , Receptores Nicotínicos/efectos de los fármacos , Animales , HumanosAsunto(s)
Hipocampo/efectos de los fármacos , Memoria/efectos de los fármacos , Nicotina/farmacología , Sinapsis/efectos de los fármacos , Acetilcolina/metabolismo , Calcio/metabolismo , Glutamina/metabolismo , Hipocampo/fisiología , Humanos , Nicotina/metabolismo , Receptores Nicotínicos/metabolismo , FumarRESUMEN
Recent studies have provided new insights into the role of presynaptic ligand-gated ion channels in modifying synaptic transmission. Along with a growing list of different types of presynaptic ionotropic receptors and the cell types that express them, there have been advances in characterizing the molecular components of the receptors as well as the signaling processes that link receptor activation to changes in neurotransmitter release. Perhaps most striking is the recent convergence of data from biochemical, molecular and electrophysiological studies, implicating presynaptic ionotropic receptors in the effects of psychoactive and addictive drugs.
Asunto(s)
Terminales Presinápticos/metabolismo , Receptores de Superficie Celular/metabolismo , Animales , Ácido Glutámico/farmacología , Humanos , Activación del Canal Iónico , Nicotina/farmacología , Receptores de Superficie Celular/efectos de los fármacos , Receptores de Superficie Celular/fisiología , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
The behavioral and cognitive effects of nicotine suggest that nicotinic acetylcholine receptors (nAChRs) participate in central nervous system (CNS) function. Although nAChR subunit messenger RNA (mRNA) and nicotine binding sites are common in the brain, there is little evidence for synapses mediated by nAChRs in the CNS. To test whether, CNS nAChRs might modify rather than mediate transmission, the regulation of excitatory synaptic transmission by these receptors was examined. Nanomolar concentrations of nicotine enhanced both glutamatergic and cholinergic synaptic transmission by activation of presynaptic nAChRs that increased presynaptic [Ca2]i. Pharmacological and subunit deletion experiments reveal that these presynaptic nAChRs include the alpha 7 subunit. These findings reveal that CNS nAChRs enhance fast excitatory transmission, providing a likely mechanism for the complex behavioral effects of nicotine.