No description available.

No description available.

No description available.

The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (IKr) that is important for cardiac repolarization. Previously, we have discovered that hERG channels rapidly internalize in low extracellular K+ ([K+]o). In cell culture, this process is driven by the endocytic protein, caveolin-1 (Cav1), which is an integral player in the caveolae-dependant endocytosis pathway. However, in the heart, Caveolin-3 (Cav3) is, in fact, the predominant form in the myocyte, and thus may play a direct role in regulating hERG expression in the heart. Thus, I hypothesize that this reduction of hERG conductance in cardiac myocytes derives from the presence of Cav3, which is integral regulator of hERG homeostasis innately in the heart. To investigate the effect of Cav3 on hERG, I overexpressed Cav3 in human embryonic kidney 293 (HEK-293) cells stably expressing hERG channels. Cav3 overexpression significantly and specifically decreased both the hERG current amplitude and the mature channel expression in normal culture conditions. Co-immunoprecipitation analysis and confocal imaging demonstrated an association between hERG and Cav3 in HEK cells as well as rat and rabbit cardiomyocytes. Mechanistically, I discovered that Cav3 possesses a faster turnover rate compared to Cav1, and can enhance hERG degradation through up-regulating mature channel ubiquitination via the ubiquitin ligase, NEDD4-2. Knockdown of Cav3 in neonatal cardiac myocytes also enhanced hERG expression. My data indicate that Cav3 participates in hERG trafficking, and is an important regulator of hERG channel homeostasis in cardiac myocytes. This information provides a platform for future intervention of the hERG-induced type-2 long QT syndrome (LQTS). / Thesis (Master, Physiology) -- Queen's University, 2011-07-28 16:42:41.304

The fragment <span lang=EN-GB style='font-family:Symbol'>b-amyloid (25-35) has sequence similarity with the tachykinin family.  It was therefore suggested that amyloid peptides might produce their effects via the tachykinin receptors.  The actions of tachykinin agonist and <span lang=EN-GB style='font-family:Symbol'>b-amyloid fragments on synaptic transmission in the rat hippocampus were explored using extracellular and whole cell patch clamp recording techniques.  Using extracellular recording techniques we examined the effect of substance P on population spikes and in particular on paired pulse depression (PPD) within the CA1 region of the hippocampus. Slices, which gave PPD on onset, showed marked changes in the amplitude of population spike on the application of substance P.  Substance P (8<span lang=EN-GB style='font-family:Symbol'>mm) produced a two-fold decrease in PPD with the second population spike increasing in amplitude.  However, substance P had little or no effect on the amplitude of the first population spike.  The use of various tachykinin receptor agonists revealed that only NK-1 receptor agonists could significantly increase the amplitude of the second population spike.  Further to this, the NK-1 receptor antagonist SR140333 blocked the action of substance P.  Therefore, it was concluded that substance P acting via the NK-1 receptor could decrease the degree of paired pulse depression observed, thereby increasing the amplitude of the second population spike. Application of <span lang=EN-GB style='font-family:Symbol'>b-amyloid (1-40)(5<span lang=EN-GB style='font-family:Symbol'>mm) produced a similar effect to substance P, having no effect on PS1, but reducing the amount of PPD.  However, the application of the neurotoxic fragment <span lang=EN-GB style='font-family:Symbol'>b-amyloid (25-35)(5, 10<span lang=EN-GB style='font-family:Symbol'>mm) which contains the sequence found in tachykinins, caused no reduction in the PPD.  The results demonstrated that the action of <span lang=EN-GB style='font-family:Symbol'>b-amyloid may depend on the length of the fragment used. Whole cell patch clamp recording revealed that substance P had no consistent effect on the passive membrane properties of the cells recorded from.  Substance P increased the amplitude of pharmacologically isolated NMDA receptor mediated EPSPs and pharmacologically isolated GABA_A receptor mediated IPSPs.  These effects are not easily reconciled with the results obtained using extracellular recordings.

Proefschrift--Utrecht. / Summary in Dutch. Bibliography: p. 101-108.

Proefschrift--Utrecht. / Summary in Dutch. Bibliography: p. 101-108.

Thesis (M.S.)--University of Wisconsin--Madison, 1983. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 22-23).

Thesis (Ph. D.)--Virginia Commonwealth University, 2010. / Prepared for: Dept. of Biomedical Engineering. Title from resource description page of electronic thesis. Include bibliographical references. Unavailable until 5/14/2015.

Thesis (M.Phil.)--Hong Kong University of Science and Technology, 2007. / Includes bibliographical references (leaves 118-129). Also available in electronic version.