Role of the C-terminal domain in the structure and function of tetrameric sodium channels.

Voltage-gated sodium channels have essential roles in electrical signalling. Prokaryotic sodium channels are tetramers consisting of transmembrane (TM) voltage-sensing and pore domains, and a cytoplasmic carboxy-terminal domain. Previous crystal structures of bacterial sodium channels revealed the nature of their TM domains but not their C-terminal domains (CTDs). Here, using electron paramagnetic resonance (EPR) spectroscopy combined with molecular dynamics, we show that the CTD of the NavMs channel from Magnetococcus marinus includes a flexible region linking the TM domains to a four-helix coiled-coil bundle. A 2.9 Å resolution crystal structure of the NavMs pore indicates the position of the CTD, which is consistent with the EPR-derived structure. Functional analyses demonstrate that the coiled-coil domain couples inactivation with channel opening, and is enabled by negatively charged residues in the linker region. A mechanism for gating is proposed based on the structure, whereby splaying of the bottom of the pore is possible without requiring unravelling of the coiled-coil

Role of the C-terminal domain in the structure and function of tetrameric sodium channels

Voltage-gated sodium channels have essential roles in electrical signalling. Prokaryotic sodium channels are tetramers consisting of transmembrane (TM) voltage-sensing and pore domains, and a cytoplasmic carboxy-terminal domain. Previous crystal structures of bacterial sodium channels revealed the nature of their TM domains but not their C-terminal domains (CTDs). Here, using electron paramagnetic resonance (EPR) spectroscopy combined with molecular dynamics, we show that the CTD of the NavMs channel from Magnetococcus marinus includes a flexible region linking the TM domains to a four-helix coiled-coil bundle. A 2.9 Å resolution crystal structure of the NavMs pore indicates the position of the CTD, which is consistent with the EPR-derived structure. Functional analyses demonstrate that the coiled-coil domain couples inactivation with channel opening, and is enabled by negatively charged residues in the linker region. A mechanism for gating is proposed based on the structure, whereby splaying of the bottom of the pore is possible without requiring unravelling of the coiled-coil

Online prostate cancer screening decision aid for at-risk men: A randomized trial

Objective: This study examines the efficacy of an online decision aid (DA) for men with a family history of prostate cancer. Methods: Unaffected Australian men (40 - 79 years) with at least one affected relative completed the first online questionnaire, were randomized to read either the tailored DA (intervention) or nontailored information about prostate cancer screening (control), then completed a questionnaire postreading and 12 months later. The primary outcome was decisional conflict regarding prostate specific antigen (PSA) testing. The impact of the DA on longitudinal outcomes was analyzed by using random intercept mixed effects models. Logistic and linear regressions were used to analyze the impact of the DA on screening behavior and decision regret. Stage of decision-making was tested as a moderator for decisional conflict and decision regret. The frequency of online material access was recorded. Results: the DA had no effect on decisional conflict, knowledge, inclination toward PSA testing, accuracy of perceived risk, or screening behavior. However, among men considering PSA testing, those who read the DA had lower decision regret compared with men who read the control materials, β=.34 , p \u3c.001, 95% confidence interval (CI) = [.22, .53]. Conclusions: This is the first study to our knowledge to evaluate the uptake and efficacy of an online screening DA among men with a family history of prostate cancer. Men who were undecided about screening at baseline benefitted from the DA, experiencing less regret 12 months later. In relation to decisional conflict, the control materials may have operated as a less complex and equally informative DA

Pressor and Sympathetic Responses to Graded Skeletal Muscle Metaboreflex Activation in Females with Relapsing-Remitting Multiple Sclerosis

Multiple sclerosis (MS) is a progressive disease characterized by demyelination in the central nervous system which disproportionately impacts females. Previous studies suggest MS-related exercise intolerance may be due to abnormal control of arterial blood pressure (BP) via the skeletal muscle metaboreflex. However, few studies have been performed and equivocal results reported. Discontinuity in prior data may be due to limited perturbation of metaboreflex activation using only low and moderate intensity exercise. PURPOSE: The purpose of this investigation was to test the hypothesis that females with MS have blunted BP and sympathetic responses to graded static handgrip (HG) exercise and isolated metaboreflex activation during postexercise ischemia (PEI) compared to healthy controls. METHODS: In 7 females with relapsing-remitting MS and 9 healthy female controls beat-to-beat BP (finometer) and muscle sympathetic nerve activity (MSNA; peroneal microneurography) were recorded at rest and during two minutes of handgrip performed at 30% and 40% maximum voluntary contraction followed by two minutes of PEI to isolate the muscle metaboreflex. RESULTS: There were no differences in resting mean arterial pressure (MAP; P= 0.16) or MSNA burst frequency (P= 0.15) between MS and controls. MAP and MSNA increased during 30% HG (MS: Δ19.8 ± 9.1 mmHg vs. Con: Δ17.8 ± 5.4 mmHg; P= 0.30 and MS: Δ17 ± 12 bursts/min vs. Con: Δ18 ± 17 bursts/min; P= 0.46) and 40% HG (MS: Δ29.3 ± 8.0 mmHg vs. Con: Δ30.0 ± 6.9 mmHg; P= 0.43 and MS: Δ36 ± 16 bursts/min vs. Con: Δ40 ± 9 bursts/min; P= 0.30) with no differences between groups. Likewise, MAP and MSNA responses were also not different during PEI post 30% HG (MS: Δ15.8 ± 7.6 mmHg vs. Con: Δ15.8 ± 6.4 mmHg; P= 0.50 and MS: Δ15 ± 9 bursts/min vs. Con: Δ11 ± 7 bursts/min; P= 0.19) or PEI post 40% HG (MS: Δ25.8 ± 6.3 mmHg vs. Con: Δ22.6 ± 8.2 mmHg; P= 0.43 and MS: Δ23 ± 13 bursts/min vs. Con: Δ24 ± 7 bursts/min; P= 0.46) between MS and controls. CONCLUSION: These preliminary data suggest intact skeletal muscle metaboreflex control of arterial BP in females with MS