RESUMEN
Background Caveolin-3 (cav-3) mutations are linked to the long-QT syndrome (LQTS) causing distinct clinical symptoms. Hyperpolarization-activated cyclic nucleotide channel 4 (HCN4) underlies the pacemaker current If. It associates with cav-3 and both form a macromolecular complex. Methods To examine the effects of human LQTS-associated cav-3 mutations on HCN4-channel function, HEK293-cells were cotransfected with HCN4 and wild-type (WT) cav-3 or a LQTS-associated cav-3 mutant (T78M, A85T, S141R, or F97C). HCN4 currents were recorded using the whole-cell patch-clamp technique. Results WT cav-3 significantly decreased HCN4 current density and shifted midpoint of activation into negative direction. HCN4 current properties were differentially modulated by LQTS-associated cav-3 mutations. When compared with WT cav-3, A85T, F97C, and T78M did not alter the specific effect of cav-3, but S141R significantly increased HCN4 current density. Compared with WT cav-3, no significant modifications of voltage dependence of steady-state activation curves were observed. However, while WT cav-3 alone had no significant effect on HCN4 current activation, all LQTS-associated cav-3 mutations significantly accelerated HCN4 activation kinetics. Conclusions Our results indicate that HCN4 channel function is modulated by cav-3. LQTS-associated mutations of cav-3 differentially influence pacemaker current properties indicating a pathophysiological role in clinical manifestations.
Asunto(s)
Potenciales de Acción , Caveolina 3/metabolismo , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/metabolismo , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/fisiopatología , Proteínas Musculares/metabolismo , Canales de Potasio/metabolismo , Caveolina 3/genética , Regulación de la Expresión Génica/fisiología , Predisposición Genética a la Enfermedad/genética , Células HEK293 , Humanos , Activación del Canal Iónico , Potenciales de la Membrana , Mutagénesis Sitio-Dirigida , Potasio/metabolismo , Relación Estructura-ActividadRESUMEN
A meta-analysis was performed to systematically assess the effect of cognitive-behavioral treatments for bulimia. To protect against past criticisms of meta-analyses, this study focused on well-defined hypotheses with clearly articulated conceptual foundations. Twenty-six studies of the cognitive-behavioral treatment of bulimia were selected through computer searches. Effect sizes were calculated for changes in behavioral outcome measures (25 independent hypothesis tests) and cognitive-attitudinal outcome measures (17 independent hypothesis tests). Additionally, two effect sizes were generated for within and between group comparisons. The analysis revealed an effect size of average r = 0.69 for behavioral outcome measures (average r = 0.64 for between group and average r = 0.74 for within group) and average r = 0.67 for cognitive-attitudinal outcome measures (average r = 0.64 for between group and average r = 0.69 for within group). Follow-up effect sizes were less favorable; however, the diversity of time spans and outcome measures used to calculate follow-up effect sizes limit their utility. Overall, results suggest that the use of a cognitive-behavioral therapy will result in favorable treatment outcomes and implications for future research are discussed.