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51.
Hong Xue 《Journal of molecular evolution》1998,47(3):323-333
The gene superfamily of ligand-gated ion channel (LGIC) receptors is composed of members of excitatory LGIC receptors (ELGIC)
and inhibitory LGIC receptors (ILGIC), all using amino acids as ligands. The ILGICs, including GABAA, Gly, and GluCl receptors, conduct Cl− when the ligand is bound. To evaluate the phylogenetic relationships among ILGIC members, 90 protein sequences were analyzed
by both maximum-parsimony and distance matrix-based methods. The strength of the resulting phylogenetic trees was evaluated
by means of bootstrap. Four major phylogenetic branches are recognized. Branch I, called BZ, for the majority of the members
are known to be related to benzodiazepine binding, is subdivided into IA, composed of all GABAA receptor α subunits, and IB, composed of the γ and ε subunits, which are shown to be tightly linked. Branch II, named NB
for non–benzodiazepine binding, and consisting of GABAA receptor β, δ, π, and ρ subunits, is further subdivided into IIA, containing β subunits; IIB, containing δ, and π subunits;
and IIC, containing ρ subunits. Branch IIIA, composed of vertebrate Gly receptors, is loosely clustered with Branch IIIB,
composed of invertebrate GluCl receptors, to form Branch III, which is designated NA for being non–GABA responsive. Branch
IV is called UD for being undefined in specificity. The existence of primitive forms of GABAA receptor non-β subunits in invertebrates is first suggested by the present analysis, and the identities of sequences p25123
from Drosophila melanogaster, s34469 from Lymnaea stagnalis, and u14635 and p41849 from C. aenorhabditis elegans are determined to be different from their previously given annotations. The proposed branching classification of ILGICs provides
a phylogenetic map, based on protein sequences, for tracing the evolutionary pathways of ILGIC receptor subunits and determining
the identities of newly discovered subunits on the basis of their protein sequences.
Received: 15 April 1997 / Accepted: 11 March 1998 相似文献
52.
Spontaneous, single channel, chloride currents were recorded in 48% of cell-attached patches on neurones in the CA1 region
of rat hippocampal slices. In some patches, there was more than 1 channel active. They showed outward rectification: both
channel conductance and open probability were greater at depolarized than at hyperpolarized potentials. Channels activated
by γ-aminobutyric acid (GABA) in silent patches on the same neurones had similar conductance and outward rectification. The
spontaneous currents were inhibited by bicuculline and potentiated by diazepam. It was concluded that the spontaneously opening
channels were constitutively active, nonsynaptic GABAA channels. Such spontaneously opening GABAA channels may provide a tonic inhibitory mechanism in these cells and perhaps in other cells that have GABAA receptors although not having a GABAA synaptic input. They may also be a target for clinically useful drugs such as the benzodiazepines.
Received: 31 August 1999/Revised: 2 November 1999 相似文献
53.
The vertebrate Cys-loop family of ligand-gated ion channels (LGICs) are comprised of nicotinic acetylcholine (nAChR), serotonin type 3 (5-HT3R), γ-aminobutyric acid (GABAAR), and glycine (GlyR) receptors. Here, we review efforts to discover selective small molecules targeting one or more Cys-loop receptors, with a focus on state-of-the-art modulators that have been reported over the past five years. Several highlighted compounds offer robust oral bioavailability and central exposure and have thus been useful in delineating pharmacokinetic/pharmacodynamic relationships in pre-clinical disease models. Others offer high levels of subtype and/or inter-superfamily selectivity and have facilitated understanding of complex SAR and pharmacodynamics. 相似文献
54.
Genomic clones from the Rdl locus of Drosophila, whose mutant phenotype is resistant to cyclodiene insecticides and picrotoxin, were characterized by restriction mapping and partial sequencing to determine intron/exon structure. The coding region of the gene comprises nine identified exons and spans greater than 25 kb of genomic DNA. The structure of the Drosophila Rdl receptor subunit was compared with those of vertebrate gamma-aminobutyric acid subtype A (GABAA) receptors and nicotinic acetylcholine receptors (nAChRs). The first six introns in Rdl show positions similar to those in vertebrate GABAA receptors, whereas the last two differ. It is interesting that the last intron appears to be in a position similar to that in nAChRs. These results are examined in relation to the proposal, based on amino acid identities, that Rdl codes for a novel class of GABAA receptor subunit more closely related to glycine receptors, and the possible place of Rdl in the lineage of the receptor superfamily is discussed. 相似文献
55.
The Cys-loop receptor family of ligand-gated ion channels (LGICs) play a key role in synaptic transmission in the central
nervous system of animals. Recent advances have led to the elucidation of two crystal structures of related prokaryotic LGICs
and the electron micrograph derived structure of the acetylcholine receptor from Torpedo marmorata. Here, we review the structural and biochemical data that form our understanding of the structure of the channel pore. We
introduce original data from the glycine receptor using the substituted-cysteine accessibility technique and show that while
the helical structure of the segment that surrounds the channel pore is generally agreed, the location of the channel gate,
the pore diameter and the structure that forms the entry to the channel pore are likely to differ between receptors. The fundamental
structural differences between anion and cation selective receptors and how these differences are related to the pore structure
are also considered. 相似文献
56.
GABAA channels were activated by GABA in outside-out patches from rat cultured hippocampal neurons. They were blocked by bicuculline
and potentiated by diazepam. In 109 of 190 outside-out patches, no channels were active before exposure to GABA (silent patches).
The other 81 patches showed spontaneous channel activity. In patches containing spontaneous channel activity, rapid application
of GABA rapidly activated channels. In 93 of the silent patches, channels could be activated by GABA but only after a delay
that was sometimes as long as 10 minutes. The maximum channel conductance of the channels activated after a delay increased
with GABA concentration from less than 10 pS (0.5 μm GABA) to more than 100 pS (10 mm GABA). Fitting the data with a Hill-type equation gave an EC
50 value of 33 μm and a Hill coefficient of 0.6. The channels showed outward rectification and were chloride selective. In the presence of
1 μm diazepam, the GABA EC
50 decreased to 0.2 μm but the maximum conductance was unchanged. Diazepam decreased the average latency for channel opening. Bicuculline, a GABA
antagonist, caused a concentration-dependent decrease in channel conductance. In channels activated with 100 μm GABA the bicuculline IC
50 was 19 μm. The effect of GABA on channel conductance shows that the role of the ligand in GABAA receptor channel function is more complex than previously thought.
Received: 23 October 2000/Revised: 27 February 2001 相似文献
57.
Purinergic Signalling - P2 receptors are present in virtually all tissues and cell types in the human body, and they mediate the physiological and pharmacological actions of extracellular purine... 相似文献