Different Subtypes Of Nicotinic Receptors Research Articles

Cytisine induces autonomic cardiovascular responses via activations of different nicotinic receptors

Nicotinic cholinergic receptors mediate autonomic transmission at ganglia. However, whether different subtypes of nicotinic cholinergic receptors expressed in autonomic ganglia elicit distinct roles in mediating sympathetic and parasympathetic regulations remain to be defined. In this study, we observed that different subtypes of nicotinic receptors were responsible for the sympathetic and parasympathetic cardiovascular responses. In urethane anesthetized mice, intravenous injection with cytisine, a non-selective nicotinic agonist, induced a brief but pronounced decrease in heart rate, followed by increases in heart rate and arterial blood pressure. The bradycardic response was blocked by atropine, and the pressor response was blocked by prazosin, confirming that these responses were parasympathetic and sympathetic activities, respectively. Hexamethonium, a ganglionic blocker, blocked both sympathetic and parasympathetic responses. Pretreatment with methyllycaconitine citrate, a selective α7 nicotinic receptor antagonist, significantly attenuated cytisine-induced sympathetic response with little effect on the parasympathetic response. In contrast, pretreatment with dihydro-β-erythroidine hydrobromide, a selective α4β2 nicotinic receptor antagonist, blocked cytisine-induced parasympathetic response but not the sympathetic response. Pretreatment with dihydro-β-erythroidine hydrobromide also blocked baroreflex associated parasympathetic bradycardic response. Moreover, treatment with nicotine induced a bradycardic response without a significant pressor response, which was also attenuated by dihydro-β-erythroidine hydrobromide. Collectively, these data suggest that different nicotinic receptors play distinct roles in sympathetic and parasympathetic ganglia. Specifically, activations of α7 and α4β2 nicotinic receptors are involved in cytisine-induced cardiovascular sympathetic and parasympathetic responses, respectively.

The neuronal nicotinic acetylcholine receptors α4* and α6* differentially modulate dopamine release in mouse striatal slices

Striatal dopamine (DA) plays a major role in the regulation of motor coordination and in the processing of salient information. We used voltammetry to monitor DA-release evoked by electrical stimulation in striatal slices, where interneurons continuously release acetylcholine. Use of the alpha6-selective antagonist alpha-conotoxin MII[E11A] and alpha4 knockout mice enabled identification of two populations of DA-ergic fibers. The first population had a low action potential threshold, and action potential-evoked DA-release from these fibers was modulated by alpha6. The second population had a higher action potential threshold, and only alpha4(non-alpha6) modulated action potential-evoked DA-release. Striatal DA-ergic neurons fire in both tonic and phasic patterns. When stimuli were applied in a train to mimic phasic firing, more DA-release was observed in alpha4 knockout versus wild-type mice. Furthermore, block of alpha4(non-alpha6), but not of alpha6, increased DA release evoked by a train. These results indicate that there are different classes of striatal DA-ergic fibers that express different subtypes of nicotinic receptors.

Pharmacology of Neuronal Nicotinic Acetylcholine Receptor Subtypes

The search for the physiological function of nicotinic receptors on neurons in the brain began with their discovery. It was initially assumed that, as in ganglia and at the neuromuscular junction, nicotinic receptors would gate fast synaptic transmission in the brain. The best functional evidence now, however, points to a role in modifying the release of other transmitters. This does not preclude a postsynaptic role in transmission for nicotinic receptors in the brain, but attempts to locate such a synapse have not been successful. If fast nicotinic synapses are present in the brain, they are probably low in number and may be masked by other more prevalent synapses (such as glutamatergic) so identification will not be easy. The extent of diversity of nicotinic receptors is substantial. At the molecular level this is reflected in the number of different genes that encode receptor subunits and the multiple possible combinations of subunits that function in expression systems. From the cellular level there is a broad diversity of properties of native receptors in neurons. Some useful pharmacological tools allow the limited identification of subunits in native receptors. For example, block by alpha-bungarotoxin identifies alpha 7, alpha 8, or alpha 9 subunits; activation of a receptor by cytisine indicates an alpha 7 or beta 4 subunit; and neuronal bungarotoxin block identifies a beta 2 subunit. Despite the clues to identity gained by careful use of these agents, we have not been able to identify all the components of any native receptor based on pharmacological properties assessed from expression studies. When both pharmacological and biophysical properties of a receptor are taken into consideration, none of the combinations tested in oocytes mimics native receptors exactly. The reason for this discrepancy has been debated at length; it is possible that oocytes do not faithfully manufacture neuronal nicotinic receptors. For example, they may not correctly modify the protein after translation or they may allow a combination of subunits that do not occur in vivo. Another possibility is that correct combinations of subunits have not yet been tested in oocytes. Data from immunoprecipitation experiments suggest that many receptors contain three or more different subunits. Results from further experiments injecting combinations of three or more subunits into oocytes may be enlightening. The diversity of receptors may allow targeting of subtypes to specific locations. Nicotinic receptors are located presynaptically, preterminally, and on the cell soma. The function of the nicotinic receptors located on innervating axons is presumably to modify the release of other neurotransmitters. It is an attractive hypothesis that nicotinic receptors might be involved in modifying the weight of central synapses; however, in none of the regions where this phenomenon has been described is there any evidence for axoaxonal contacts. The presynaptic receptors described so far are pharmacologically unique; therefore, if there are different subtypes of nicotinic receptors modifying the release of different transmitters, they may provide a means of exogenously modifying the release of a particular transmitter with drugs. There are still many basic unanswered questions about nicotinic receptors in the brain. What are the compositions of native nicotinic receptors? What is their purpose on neurons? Although there is clearly a role presynaptically, what is the function of those located on the soma? Neuronal nicotinic receptors are highly permeable to calcium, unlike muscle nicotinic receptors, and this may have important implications for roles in synaptic plasticity and development. Finally, why is there such diversity? (ABSTRACT TRANCATED)

Nicotinic acetylcholine receptor subtypes in human frontal cortex: Changes in Alzheimer's disease

Molecular genetic and pharmacological studies have suggested that several subtypes of nicotinic acetylcholine receptors exist in the mammalian and avian brain. Combining 3H-(-)-nicotine, 125I-alpha-bungarotoxin, and 125I-kappa-bungarotoxin as ligands, we report here the first evidence for the existence in human frontal cortex of at least three different subtypes of nicotinic receptors. Autoradiographic analysis shows that specific 125I-kappa-bungarotoxin binding sites are concentrated mainly in several cortical layers. We also show that kappa-bungarotoxin, but not alpha-bungarotoxin decreases the evoked release of 3H-acetylcholine in rat cortical slices, indicating a likely presynaptic localization for some of the alpha-bungarotoxin-insensitive kappa-bungarotoxin sites in mammalian brain. The brains of patients with Alzheimer's disease show marked decreases in Bmax values for low-affinity 125I-kappa-bungarotoxin sites and both high- and low-affinity 3H-nicotine sites, whereas 125I-alpha-bungarotoxin sites are not significantly different in number from age-matched control brains. We conclude that Alzheimer's disease does not affect all subtypes of nicotinic receptors in the frontal cortex to the same extent.