RESUMO
Nicotinic acetylcholine receptors (nAChRs) are widely expressed in the mammalian central nervous system (CNS). Despite this, very little was known, until recently, about their physiological role. In the periphery, nicotinic receptors mediate vital excitatory fast synaptic cholinergic transmission at both the neuromuscular junction and ganglia. In the brain, this role has been mainly "delegated" to glutamate receptors. The very broad cholinergic innervations of most brain areas, including the cortex, have implicated this system, and brain nicotinic receptors in particular, in a unique "modulatory" role of other transmitters systems. Recent evidence confirms, on one hand, that brain nicotinic receptors have a dominant "presynaptic" modulatory function, controlling the release of both acetylcholine (auto-receptors) and other neurotransmitters (hetero-receptors). On the other hand, more experimental data support the idea that a variable component of fast synaptic transmission in the brain can also be mediated by "postynaptic" nicotinic receptors, which, in turn, can control cell excitability. A challenging goal is to identify which one of the plethora of nicotinic receptor subtypes is mediating each effect in different brain areas, and which of these receptors and functions are lost or affected in different human neuro-psychiatric disorders. Needless to say, a better understanding of the physiological role of brain nicotinic receptors will drive our quest for more selective and efficacious nicotinic receptor targeted therapeutic agents.
Assuntos
Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Neurotransmissores/metabolismo , Receptores Nicotínicos/fisiologia , Transmissão Sináptica/fisiologia , Animais , Humanos , Receptores Nicotínicos/classificação , Receptores Nicotínicos/metabolismoRESUMO
The effects of 5-hydroxyindole (5-HI) have been investigated on human alpha 7 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes and GH4 cells, on native alpha 7 nAChRs expressed by IMR-32 cells and on alpha 7 nAChR-mediated events in mossy fibre-granule cell synapses in rat cerebellar slices. In oocytes expressing alpha 7 nAChRs, 5-HI potentiated sub-maximal, 60 micro M ACh-induced ion currents in a concentration-dependent manner, the threshold effective concentration being 30 micro M. 5-HI itself did not act as an agonist on alpha 7 nAChRs. A maximum potentiation of 12 times the control was observed at 20 mM 5-HI. The effect of 1 mM 5-HI on the concentration-response curve for ACh revealed that 5-HI increased the potency as well as the efficacy of ACh on alpha 7 nAChRs. 5-HI also potentiated alpha 7-mediated increases in intracellular free calcium levels in both mammalian cells heterologously expressing human alpha 7 nAChRs and in human IMR-32 neuroblastoma cells expressing native alpha 7 nAChRs. At mossy fibre-granule cell synapses, application of 1 mM ACh induced glutamate-evoked excitatory post-synaptic currents (EPSCs). Co-application of 1 mM 5-HI with 1 mM ACh further increased the frequency of the EPSCs. The ACh-induced release, as well as the 5-HI-induced enhancement of release, were blocked by 1-10 nM methyllycaconitine or 200 nM alpha-bungarotoxin, demonstrating that both effects were mediated by presynaptic alpha 7 nAChRs. The results demonstrate that responses mediated by alpha 7 nAChRs are strongly potentiated by 5-HI.