Mini reviewNicotinic acetylcholine receptors in autonomic ganglia
Introduction
Nicotinic acetylcholine receptors (nAChRs) are the members of a gene superfamily of ionotropic that are formed by five homologous subunits oriented around a central ionic channel. This superfamily includes, in addition to nAChRs, 5-HT3 receptors, GABAA receptors and glycine receptors, but not structurally different glutamate receptors and purinoreceptors (see Lindstrom, 1996). The nAChRs are known to mediate fast synaptic transmission in centrifugal and peripheral reflex pathways of all autonomic ganglia and plexuses. Although some recent results suggest this function can also be fulfilled by some other receptors, e.g., P2x purinoreceptors (Evans et al., 1992; see for review Galligan and Bertrand, 1994), or 5-HT3 (serotonin) receptors (Derkach et al., 1989; see for review Khakh and Henderson, 2000), the evidence for their role in fast transmission in normal (non-cultured) ganglion neurons is still scarce. Although nAChRs are abundantly located in the central nervous system (CNS), most electrophysiological approaches failed to demonstrate their mediatory role in fast synaptic transmission, except in Renshaw cells (see, however, Zaninetti et al., 1999, Marrubio et al., 1999). This peculiarity suggests that nAChRs in CNS may be involved in some forms of nonsynaptic neurotransmission (Vidal and Changeux, 1996). Interestingly, most recent studies showed that, in addition to postsynaptic localization, some nAChRs are localized on terminal buttons, and can cause a significant calcium influx in the buttons, thus modulating the neurotransmitter release (see Itier and Bertrand, 2001 for review).
The fact that nAChRs mediate synaptic transmission in autonomic pathways which greatly differ in their modality (e.g., vasomotor, secretory, etc.) and localization (e.g., vasomotor pathways to the head and extremities), raises a question whether or not there is a correlation between the nAChR structure and pharmacology, on one hand, and modality of the corresponding pathways, on the other hand. This review focuses on recent studies concerning structure and functions of nAChRs located in autonomic ganglia, including their subunit content and structure, agonist binding, and channel properties. For more detailed characteristics of neuronal nAChRs other than those in autonomic ganglia, see reviews (e.g., Conti-Fine et al., 1995, Lindstrom, 1996, McGehee, 1999, Paterson and Nordberg, 2000, Itier and Bertrand, 2001).
Section snippets
Subunit composition of autonomic nAChRs
Three main ways were used to identify the nAChR subunits expressed in neurons: genetic, immunological and pharmacological. The genetic way (RT-PCR, in situ hybridization) allowed the researchers to identify the nAChR mRNAs, i.e., the genes expressed. The immunological way was to use the subunit-specific antibodies to identify the proteins expressed (immunocytochemical staining or Western blotting). Alternatively, the antibodies directed to the agonist-binding domain were used as selective
The ACh binding site
The amino acid sequence analysis of different α subunits (see Galzi et al., 1990, Galzi et al., 1991, Galzi et al., 1996) showed that tryptophan 86, tyrosine 93, tryptophan 149, tyrosine 190, cysteine 192, cysteine 193 and tyrosine 198 are highly conservative in α1 (muscle), α2, α3 and α4 (neuron) subunits. The role of conserved amino acids in ligand binding and subsequent ion channel opening was investigated using two main approaches: (1) a site-directed mutagenesis of different nAChR subunits
Channel kinetics in autonomic nAChRs
Each neuron of an autonomic ganglion expresses a few groups of nAChRs characterized with different channel kinetics. The first evidence for this was obtained by Rang (1981), who found a two-exponential decay of the excitatory postsynaptic current (EPSC) evoked in rat submandibular ganglion neurons by single preganglionic stimulus, with mean time constants ranging from 5 to 9 and from 27 to 45 ms for fast and slow EPSC components, respectively, as found at −50 mV holding potential and room
Channel conductance in autonomic nAChRs
An early study of single channel conductance using the cell-attached patch-clamp recording method revealed in non-dissociated neurons of rat SCG two channel populations, with mean conductance 20.0 and about 50 pS (Derkach et al., 1987). The former group of channels was much more numerous than the latter one, and this channel conductance varied within a range found in many other mammalian, avian and amphibian autonomic ganglia (from 16.9 to 42 pS: see for review Skok et al., 1989).
The α3β4
Channel dimensions in autonomic nAChRs
Assuming that the channel-blocking molecule of a longitudinal shape (a bis-cationic ammonium compound, the pentamethonium or pentaethonium derivative) approaches the channel with its longitudinal axis perpendicular to the a membrane, the channel cross-profile at the level where the channel is relatively narrow (a channel shaft) was estimated from the correlation between the cross-profile of the blocking molecule used as a tool, and its blocking activity. The best correlation was observed with
Channel architecture in autonomic nAChRs
The data about the structure of nAChR channel were mainly obtained from the α7 subunit homomers expressed in heterologous objects, and are applicable to the autonomic ganglia, as the α7 subunit-containing nAChRs are widely spread in the ganglia. The ionic channel of a nAChR is supposed to be formed by M2 transmembrane segments, which are α-helices. It was shown using a site-directed mutagenesis that the amino acid residues of the segments form several rings responsible for binding of the
A receptor-to-receptor interaction of autonomic nAChRs
In most neurons of the guinea-pig submucous plexus, both exogenous ACh and adenosine-triphosphate (ATP) evoke an inward membrane current. If applied during the ATP current, ACh evokes reduced current, and ACh plus ATP current does not exceed the ATP current only. No such effects of ATP on the ACh current in observed in the submucous neurons, which do not respond to ATP, i.e., are devoid of the ATP receptors. These results suggest that there is an interaction between nAChRs and ATP receptors
Modulation of autonomic nAChR activity by intracellular messengers
The activity of many ligand-gated membrane channels is known to be strongly influenced by intracellular messengers through phosphorylation of cytoplasmic part of their molecules. A detailed study of the guinea-pig submucous neurons showed (Glushakov et al., 1999) that the ACh currents were not affected by forskolin, the adenylate cyclase activator, regardless of whether ATP and GTP were present in the intracellular solution. Forskolin is known to elevate intracellular cAMP level in several
Pharmacological specificity of autonomic nAChRs
It has long been known that neuronal nAChRs of different autonomic ganglia and plexuses differ in their sensitivity to blocking drugs from each other and from nAChRs of the central nervous system (for review see, e.g., Skok et al., 1989). One of the most striking examples is that nAChRs of rat cardiac neurons activated by exogenous ACh are much less sensitive to conventional ganglionic blocking drugs hexamethonium, d-tubocurarine and trimetaphan (IC50=226, 31.2 and 15.3 μM, respectively
Summary
Although α3β4 subunit combination is clearly prevalent in the nAChRs of autonomic ganglia neurons, the ganglia are strikingly different in the ratio of neurons containing each particular nAChR subunit, as found with immunohistochemical methods and from the analysis of the effects of nAChR subunit-specific antibodies on the ACh-induced membrane currents. In particular, the number of neurons containing α3, α4, α5 or α7 subunits is by about three times higher in sympathetic ganglia than in
References (131)
- et al.
Alpha-conotoxins
Int. J. Biochem. Cell Biol.
(2000) - et al.
Effect of MK-801 at the human alpha-7 nicotinic acetylcholine receptor
Neuropharmacology
(1996) - et al.
Leu10 of alpha-conotoxin PnIB confers potency for neuronal nicotinic responses in bovine chromaffin cells
Eur. J. Pharmacol.
(2000) - et al.
Characterization of the recombinant human neuronal nicotinic acetylcholine receptors alpha-3 beta-2 and alpha-4 beta-2 stably expressed in HEK293 cells
Neuropharmacology
(2000) - et al.
Pharmacology of neuronal nicotinic acetylcholine receptor subtypes
Adv. Pharmacol.
(1997) - et al.
Neurons can maintain multiple classes of nicotinic acetycholine receptors distinguished by different subunit compositions
J. Biol. Chem.
(1995) - et al.
Mutational analysis of the charge selectivity filter of the alpha-7 nicotinic acetylcholine receptor
Neuron
(1999) - et al.
Desnitroimidaclorid and nicotine binding site in rat recombinant alpha-4 beta-2 neuronal nicotinic catylcholine receptor
Pestic. Biochem. Physiol.
(1999) - et al.
Characterisation of the binding of [3H] methyllycaconitine: a new radioligand for labelling alpha7-type neuronal nicotinic acetylcholine receptors
Neuropharmacology
(1999) - et al.
Regions of beta-4, beta-2 subunit chimera that contribute to the agonist selectivity of neuronal nicotinic receptors
FEBS Lett.
(1992)
MK-801 blocks nicotinic depolarizations of guinea pig myenteric neurones
Neurosci. Lett.
Neurotransmitter-gated ion channels as unconventional allosteric proteins
Curr. Opin. Struct. Biol.
Neuronal nicotinic receptors molecular organization and regulations
Neuropharmacology
Identification of a novel amino acid a tyrosine 93 within the cholinergic ligand-binding sites of the acetylcholine receptor by photoaffinity labeling
J. Biol. Chem.
Functional significance of aromatic amino acids from three peptide loops of the alpha-7 neuronal nicotinic receptor site investigated by site directed mutagenesis
FEBS Lett.
Modulation of nicotinic acetylcholine receptor activity in submucous neurons by intracellular messengers
JANS
Drugs selectiva for nicotinic receptor subtypes: a real possibility or a dream?
Behav. Brain Res.
Single amino acid substitutions in alpha-conotoxin PnIA shift selectivity for subtypes of the mammalian neuronal nicotinic acetylcholine receptor
J. Biol. Chem.
Lack of evidence for P2X-purinoceptor involvement in fast synaptic responses in intact sympathetic ganglia isolated from guinea-pigs
Neuroscience
Neuronal nicotinic receptors: from protein structure to function
FEBS Lett.
Modulation of fast synaptic transmission by presynaptic ligand-gated cation channels
JANS
Mechanism of long-lasting block of ganglion nicotinic receptors by mono-ammonium compounds with long aliphatic chain
JANS
Minimal conformation of the alpha-conotoxin ImI for the alpha-7 neuronal nicotinic acetylcholine receptor recognition: correlated CD, NMR and binding studies
FEBS Lett.
Forskolin: a specific stimulator of adenylyl cyclase or a diterpene with multiple sites of action?
Trends Pharmacol. Sci.
Chimeric analysis of a neuronal nicotinic acetylcholine receptor reveals amino acids conferring sensitivity to alpha-bungarotoxin
J. Biol. Chem.
Characterization of nicotinic acetylcholine receptors expressed by cells of the SH-SY5Y human neuroblastoma clonal line
Mol. Cell. Neurosci.
Conus peptides: novel probes for nicotinic acetylcholine receptor structure and function
Eur. J. Pharmacol.
Mutational analysis of ligand-induced activation of the torpedo acetylcholine receptor
J. Biol. Chem.
Neuronal nicotinic receptors in the human brain
Prog. Neurobiol.
Diversity, in primary structure and function of neuronal nicotinic acetylcholine receptor channels
Curr. Opin. Neurobiol.
Targeting alpha-7 containing nicotinic receptors on neurons to distal locations
Eur. J. Pharmacol.
Nicotinic receptor function in the mammalian nervous system
Ann. N. Y. Acad. Sci.
Neuronal nicotinic receptors modulate synaptic function in the hippocampus and are sensitive to blockade by the convulsant strychnine and by the anti-Parkinson drug amantadine
Toxicol. Lett.
Diversity of nicotinic acetylcholine receptors in the brain: V. Alpha-bungarotoxin-sensitive nicotinic receptors in olfactory bulb neurons and presynaptic modulation of glutamate release
J. Pharmacol. Exp. Ther.
Choline is a selective agonist of alpha-7 nicotinic acetylcholine receptors in the rat brain neurons
Eur. J. Neurosci.
Ultrastructural localization of the alpha-4-subunit of the neuronal acetylcholine nicotinic receptor in the rat substantia nigra
J. Neurosci.
Functional nicotinic acetylcholine receptors that mediate ganglionic transmission in cardiac parasympathetic neurons
J. Neurosci.
Involvement of a phorbol-in-sensitive protein kinase C in the p2-adrenergic inhibition of voltage-gated calcium current in chick sympathetic neurons
J. Neurosci.
Stoichiometry of human recombinant neuronal nicotinic receptors containing the beta-3 subunit expressed in Xenopus oocytes
J. Physiol.
The alpha-7 nicotinic acetylcholine receptor in neuronal plasticity
Mol. Neurobiol.
Architecture of the neuronal nicotinic acetylcholine receptor ion channel at the binding site of bis-ammonium blockers
J. Membr. Biol.
Open-channel blockers at the human alpha-4 beta-2 neuronal nicotinic acetylcholine receptor
Mol. Pharmacol.
Beta-subunits co-determine the sensitivity of rat neuronal nicotinic receptors to antagonists
Pfluegers Arch.-Eur. J. Physiol.
Characteristics of fasic and ionic sympathetic ganglia cells of the guinea-pig
J. Physiol.
Nicotinic acetylcholine receptors containing alpha-7subunits are required for reliable synaptic transmission in situ
J. Neurosci.
The principles of the stochastic interpretation of ion-channel mechanisms
Alpha-3, beta-2, and beta-4 form heterotrimeric neuronal nicotinic acetylcholine receptos in Xenopus oocytes
J. Neurochem.
Binding sites for neurotoxins and clolinergic ligands in peripheral and neuronal nicotinic receptors
Ann. N. Y. Acad. Sci.
Coexpression of multiple acetylcholine receptor genes in neurons. Quantification of transcripts during development
J. Neurosci.
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