The receptor for the inhibitory neurotransmitter glycine is a member of the ligand-gated ion channel receptor superfamily.
Point mutations in the gene encoding the alpha 1 subunit of the glycine ...receptor-channel complex (GlyR) have recently been
identified in pedigrees with the autosomal dominant neurological disorder, startle disease (hyperekplexia). These mutations
result in the substitution of leucine or glutamine for arginine 271. This charged residue is located near the ion channel
region and is predicted to affect chloride permeation through the GlyR. We found little evidence for this role from the anion/cation
selectivity and lack of pronounced rectification of currents flowing through recombinant human alpha 1 subunit GlyRs containing
the startle disease mutations. We reveal, however, that the startle disease mutations profoundly disrupt GlyR function by
causing 230-410-fold decreases in the sensitivity of receptor currents activated by the agonist glycine. Additionally, we
report corresponding 56- and 120-fold reductions in the apparent binding affinity (Ki) of glycine to the mutant GlyRs, but
no change in the binding affinity of the competitive antagonist, strychnine. Thus, startle disease reduces the efficacy of
glycinergic inhibitory neurotransmission by producing GlyRs with diminished agonist responsiveness. Our results show that
startle disease mutations define a novel receptor activation site.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A loop structure, formed by the putative disulfide bridging of Cys198 and Cys209, is a principal element of the ligand binding site in the glycine receptor (GlyR). Disruption of the loop's tertiary ...structure by Ser mutations of these Cys residues either prevented receptor assembly on the cell surface, or created receptors unable to be activated by agonists or to bind the competitive antagonist, strychnine. Mutation of residues Lys200, Tyr202 and Thr204 within this loop reduced agonist binding and channel activation sensitivities by up to 55‐, 520‐ and 190‐fold, respectively, without altering maximal current sizes, and mutations of Lys200 and Tyr202 abolished strychnine binding to the receptor. Removal of the hydroxyl moiety from Tyr202 by mutation to Phe profoundly reduced agonist sensitivity, whilst removal of the benzene ring abolished strychnine binding, thus demonstrating that Tyr202 is crucial for both agonist and antagonist binding to the GlyR. Tyr202 also influences receptor assembly on the cell surface, with only large chain substitutions (Phe, Leu and Arg, but not Thr, Ser and Ala) forming functional receptors. Our data demonstrate the presence of a second ligand binding site in the GlyR, consistent with the three‐loop model of ligand binding to the ligand‐gated ion channel superfamily.
Sexual aggression in dating is now a widespread social phenomenon. The present study was designed to examine interpretations in a sexual disagreement situation within young dating couples. Forty-five ...heterosexual couples classified into one of three distinct stages of involvement were asked to complete several questionnaires requesting background and sexual information, and respond to six brief scenarios describing dating situations. It was hypothesized that the respondent's sex, couple's dating stage, woman's type of "No" response, and the level of intimacy were related to the following: a man's reaction to his date's refusal of unwanted sexual advances, and any future consequences to the couple's dating relationship. Results from MANOVAs and ANOVAs indicated that while many men, in general, would comply with a date's refusal, a substantial percentage of men would use some type of coercion to continue advances after a woman refused. Each man's compliance was found to be influenced by the particular dating stage and intimacy level in which he and his partner were involved. These findings indicate the dating situation is highly complex and susceptible to misinterpretation.
To provide an overview of the current approaches to management of renovascular disease.
A literature review was performed and key references are provided relating to diagnostic tests, particularly ...captopril renography and renal duplex scanning. Options for treatment are reviewed from published series to December 1991. We also draw on the experience of our own Unit.
Data and opinions from five general reviews of renovascular disease, 10 articles on diagnostic tests and five articles relating to therapeutic approaches are summarised.
There is no simple screening test for renovascular hypertension that can be applied to an unselected population of hypertensive subjects. The diagnosis depends on judicious use of non-invasive screening tests in those subjects in whom one suspects, on clinical grounds, that there may be an underlying renovascular lesion. Captopril renography and duplex scanning of renal arteries are the most reliable non-invasive screening tests. A team approach with collaboration of hypertension specialist/vascular physician, vascular surgeon and experienced interventional radiologist is important for rational management and we would emphasise the importance of audit procedures.
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