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Biomedical subjects

S Brandon

Publications and source records attributed to S Brandon.

At least 37 records · Page 2Linked to original sources
PubMed1994

Coupling of the alpha 2A-adrenergic receptor to multiple G-proteins. A simple approach for estimating receptor-G-protein coupling efficiency in a transient expression system.

It is now widely appreciated that G-protein-coupled cell-surface receptors can modulate distinct signal transduction pathways via coupling to different GTP-binding proteins. In the present study, we have used a transient co-expression approach to study the coupling of a single alpha 2-adrenergic receptor (alpha 2AAR) population to three different G protein subtypes (Gi, Gq, and Gs) acting on two different cellular effectors in HEK 293 cells. In all cases, the affinity of the receptor for the alpha 2A-adrenergic agonist, UK14304, is unchanged (KD approximately equal to 670 nM). However, there is a dramatic difference in the EC50 of UK14304 in eliciting inhibition of endogenous adenylyl cyclase via endogenous Gi (0.09 nM) versus activation of phospholipase C via co-transfected Gq (50 nM) or stimulation of endogenous adenylyl cyclase via co-transfected Gs (70 nM) in HEK 293 cells. These findings are consistent with the interpretations that the alpha 2AAR preferentially interacts with Gi rather than Gs or Gq. When the alpha 2AAR was mutated at Asp79, a residue highly conserved among G-protein-coupled receptors, the mutant D79N alpha 2AAR lost the ability to couple to Gq and Gs and, although it was able to couple to inhibition of cyclase via pertussis toxin-sensitive pathways (Gi), it did so with a lower potency than observed for the wild-type alpha 2AAR (EC50 = 7.2 nM). The most straightforward interpretation of these data is that the D79N mutation in the alpha 2AAR reduces the efficiency of coupling of the alpha 2AAR to all G-proteins, thus eliminating signal transduction through those pathways less efficiently coupled to the alpha 2AAR. Since the transient expression assays described permit manipulation of the structure of both the receptor or the G-protein, the present strategies could be exploited to delineate the complementary domains specifying the affinity and/or efficacy of receptor coupling to distinct GTP-binding proteins.

Adenylyl Cyclase Inhibitors↗
PubMed1993

Panic disorder: clinical perspectives.

The evolution of the concept of panic disorder is described and its utility in identifying treatment strategies outlined. Some data are provided which may account for the female preponderance in diagnosed cases. In discussing the continuing role of benzodiazepines the curious history of their progressive restriction in Britain is described. Component and cluster analysis of the phenomena associated with panic attacks provides unexpected support for Klein's theory linking the disorder with an evolved alarm mechanism for suffocation. Current concepts on treatment are briefly reviewed.

Adolescent↗
PubMed1993

Subtyping of panic disorder by symptom profile.

During Phase II of the Cross-National Panic Study, descriptions of the patient's last severe panic attack were collected for 1168 patients. Statistical analysis indicated that patients could be divided into two groups, characterised by the presence or absence of prominent respiratory symptoms. The two groups did not differ on demographic variables or coexisting diagnoses, but they did differ on psychopathology on entry to the study and treatment outcome. The group with prominent respiratory symptoms suffered more spontaneous panic attacks and responded to imipramine, whereas the group without prominent respiratory symptoms suffered more situational panic attacks and responded more to alprazolam. It is important to distinguish spontaneous and situational panic attacks, to aid choice of treatment.

Adult↗
PubMed1992

Synthesis of a yohimbine-agarose matrix useful for large-scale and micropurification of multiple alpha 2-receptor subtypes.

We have provided a detailed protocol for the synthesis of a yohimbine-agarose matrix that has been shown to be effective for isolation of the alpha 2A-adrenergic receptor from human platelet and purification of the alpha 2A-adrenergic receptor to apparent homogeneity from porcine brain cortex using chromatography on only two sequential yohimbine-agarose columns. In addition, this affinity matrix also interacts with alpha 2 receptors of the alpha 2B subtype extracted from cultured NG108-15 cells. Finally, this affinity matrix has proven useful for monitoring posttranslational modifications of the receptor in digitonin extracts of metabolically labeled cells. Thus, this affinity matrix can be exploited for the purification of multiple alpha 2-adrenergic receptor subtypes on both a macro- and microscale and should be of value to any laboratory exploring the molecular basis for alpha 2-adrenergic functions.

Adrenergic alpha-Agonists↗
PubMed1992

Who benefits from electroconvulsive therapy? Combined results of the Leicester and Northwick Park trials.

This paper describes the results obtained by combining data from the Northwick Park and Leicester randomised controlled trials of ECT. Patients who suffered from depression in which retardation and delusions were features and who received real ECT had a significantly improved outcome at the end of four weeks of treatment (as measured by improvement in the HRSD) in comparison with those who received simulated ECT. However, this treatment effect was not detectable at six-month follow-up. Patients who were neither retarded nor deluded did not benefit significantly from real as opposed to simulated ECT.

Antidepressive Agents↗
PubMed1991

Subtyping panic disorder by major depression and avoidance behaviour and the response to active treatment.

In order to establish the clinical validity of currently used ways of subtyping panic disorder the predictive power of associated current avoidance behaviour and (secondary) major depression for the response to active treatment (alprazolam, imipramine) was tested. The analysis was based on the data from the Cross-National-Collaborative-Panic-Study. Limited support for validity evidenced by predicting drug response was found for grading panic disorder by the severity of avoidance behaviour; patients with panic attacks and agoraphobia are more responsive to imipramine (compared with alprazolam) when using the reduction of the total number of panic attacks (or of spontaneous panic attacks) as the outcome criterion; patients without any avoidance behaviour did better with alprazolam (compared with imipramine).

Adult↗
PubMed1991

Avoidance behaviour: a predictor of the efficacy of pharmacotherapy in panic disorder?

The impact of the avoidance behaviour on the psychopharmacological treatment of panic disorder was explored in the Cross National Collaborative Panic Study (n = 1134 patients); in this double blind randomized trial alprazolam, imipramine and placebo were compared during an 8-week treatment period. Patients with extensive avoidance behaviour (agoraphobia) had the most profit from the active drugs. Counter expectancy these specific drug effects were most pronounced in avoidance behaviour. Active drugs (in particular imipramine) were especially more effective than placebo if the patients presented with associated avoidance behaviour. The results suggest that agoraphobia defines more a particular type of anxiety disorder overlapping with panic disorder than merely a severe state of panic disorder.

Adult↗
PubMed1991

Monovalent cation and amiloride analog modulation of adrenergic ligand binding to the unglycosylated alpha 2B-adrenergic receptor subtype.

The unglycosylated alpha 2B subtype of the alpha 2-adrenergic receptor found in NG-108-15 cells possesses allosteric regulation of adrenergic ligand binding by monovalent cations and 5-amino-substituted amiloride analogs. These findings demonstrate that allosteric modulation of adrenergic ligand binding is not a property unique to the alpha 2A subtype. The observation that amiloride analogs as well as monovalent cations can modulate adrenergic ligand binding to the nonglycosylated alpha 2B subtype indicates that charge shielding due to carbohydrate moieties does not play a role in this allosteric modulation but, rather, these regulatory effects result from interactions of cations and amiloride analogs with the protein moiety of the receptor. Furthermore, the observation that both alpha 2A and alpha 2B receptor subtypes are modulated by amiloride analogs suggests that structural domains that are conserved between the two are likely to be involved in this allosteric modulation.

Amiloride↗
PubMed1990

An aspartate conserved among G-protein receptors confers allosteric regulation of alpha 2-adrenergic receptors by sodium.

The residue involved in sodium regulation of G-protein-coupled receptors has been identified by site-directed mutagenesis of the alpha 2-adrenergic receptor gene. Mutation of Asp-79 to Asn-79 entirely eliminates allosteric regulation of ligand binding by monovalent cations without perturbing the selectivity of adrenergic binding or allosteric modulation of that binding by amiloride analogs. The high degree of conservation of this aspartate residue in all G-protein-coupled receptors, without even a conservative change to glutamate, underscores the probable importance of this allosteric regulation.

Affinity Labels↗
PubMed1989

NHS indemnity.

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Humans↗
PubMed1989

Avoidance behaviour and major depression in panic disorder: a report from the Cross-National Collaborative Panic Study.

Avoidance behaviour and secondary major depression are both frequent in clinical samples of patients with panic disorder. Their status is unclear: indicators of severity of panic disorder or indicators of separate psychiatric disorders. Among the data of the Cross-National Collaborative Panic Study (n = 1,168) we found that especially avoidance behaviour defines more severe states of panic disorder (earlier age at onset, higher frequency of panic attacks and higher level of psychopathology); co-occurrence of major depression is less clearly associated with more severe panic disorder. The results are compatible with the DSM-III-R concepts of comorbidity of panic disorder and major depression and of subtyping panic disorder by avoidance behaviour.

Adult↗