Voltage-gated calcium channels (VGCCs) are transmembrane proteins that translate electrical activities into intracellular calcium elevations and downstream signaling pathways. They serve essential ...physiological functions including communication between nerve cells, muscle contraction, cardiac activity, and release of hormones and neurotransmitters. Asparagine-linked glycosylation has emerged as an essential post-translational modification to control the number of channels embedded in the plasma membrane but also their functional gating properties. This review provides a comprehensive overview about the current state of knowledge on the role of glycosylation in the expression and functioning of VGCCs, and discusses how variations in the glycosylation of the channel proteins can contribute to pathological conditions.
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•Voltage-gated calcium channels are glycosylated.•N-glycosylation modulates expression and activity of the channels.•Altered N-glycosylation may contribute to diseased states associated with the channels.
Worldwide, rivaroxaban is increasingly used for stroke prevention in atrial fibrillation and treatment of venous thromboembolism, but little is known about rivaroxaban-related bleeding complications ...in daily care. Using data from a prospective, noninterventional oral anticoagulation registry of daily care patients (Dresden NOAC registry), we analyzed rates, management, and outcome of rivaroxaban-related bleeding. Between October 1, 2011, and December 31, 2013, 1776 rivaroxaban patients were enrolled. So far, 762 patients (42.9%) reported 1082 bleeding events during/within 3 days after last intake of rivaroxaban (58.9% minor, 35.0% of nonmajor clinically relevant, and 6.1% major bleeding according to International Society on Thrombosis and Haemostasis definition). In case of major bleeding, surgical or interventional treatment was needed in 37.8% and prothrombin complex concentrate in 9.1%. In the time-to-first-event analysis, 100-patient-year rates of major bleeding were 3.1 (95% confidence interval 2.2-4.3) for stroke prevention in atrial fibrillation and 4.1 (95% confidence interval 2.5-6.4) for venous thromboembolism patients, respectively. In the as-treated analysis, case fatality rates of bleeding leading to hospitalizations were 5.1% and 6.3% at days 30 and 90 after bleeding, respectively. Our data indicate that, in real life, rates of rivaroxaban-related major bleeding may be lower and that the outcome may at least not be worse than that of major vitamin K antagonist bleeding, and probably better. This trial was registered at www.clinicaltrials.gov as identifier #NCT01588119.
•In a real-world setting, annualized bleeding rates of major rivaroxaban bleeding are lower than those reported for vitamin K antagonists.•Treatment of major rivaroxaban bleeding is simple and rarely requires pro-coagulants; outcome at 90 days is better than that reported for vitamin K antagonists.
Amyotrophic lateral sclerosis (ALS) stands as the most prevalent and severe form of motor neuron disease, affecting an estimated 2 in 100,000 individuals worldwide. It is characterized by the ...progressive loss of cortical, brainstem, and spinal motor neurons, ultimately resulting in muscle weakness and death. Although the etiology of ALS remains poorly understood in most cases, the remodelling of ion channels and alteration in neuronal excitability represent a hallmark of the disease, manifesting not only during the symptomatic period but also in the early pre-symptomatic stages. In this review, we delve into these alterations observed in ALS patients and preclinical disease models, and explore their consequences on neuronal activities. Furthermore, we discuss the potential of ion channels as therapeutic targets in the context of ALS.
Abstract
Low-voltage-activated Ca
v
3 calcium channels (T-type) play an essential role in the functioning of the nervous system where they support oscillatory activities that relie on several channel ...molecular determinants that shape their unique gating properties. In a previous study, we documented the important role of the carboxy proximal region in the functioning of Ca
v
3.3 channels. Here, we explore the ability of a TAT-based cell penetrating peptide containing this carboxy proximal region (TAT-C3P) to modulate the activity of Ca
v
3 channels. We show that chronic application of TAT-C3P on tsA-201 cells expressing Ca
v
3 channels selectively inhibits Ca
v
3.3 channels without affecting Ca
v
3.1 and Ca
v
3.2 channels. Therefore, the TAT-C3P peptide described in this study represents a new tool to address the specific physiological role of Ca
v
3.3 channels, and to potentially enhance our understanding of Ca
v
3.3 in disease.
Drug-coated balloons (DCBs) for femoropopliteal interventions have not been tested against each other. We aimed to directly compare efficacy and safety of a high-dose (In.Pact™) vs. low-dose ...(Ranger™) DCB with nominal paclitaxel densities of 3.5 vs. 2.0 μg/mm2.
Within a prospective, multicentre, non-inferiority, clinical trial 414 patients with symptomatic femoropopliteal lesions (Rutherford classification 2-4) were randomly assigned in a 1:1 ratio to endovascular treatment with either high- or low-dose DCB after stratification for lesion length. Primary efficacy and safety endpoints comprised primary patency and freedom from major adverse events (i.e. device and procedure-related deaths through 1 month, major amputations, and clinically driven target lesion revascularization through 12 months). We set a non-inferiority margin of -10% at 12 months. Total occlusions were observed frequently (>40%) and provisional stenting was performed in every fourth intervention. Non-inferiority was determined for both primary efficacy and safety endpoints at 12 months. Primary patency was 81.5% in the high-dose and 83.0% in low-dose DCB group {difference: 1.5% lower bound of the 90% two-sided confidence interval (CI) -5.2%; Pnon-inferiority < 0.01}. Freedom from major adverse events was determined in 92.6% in high-dose and in 91.0% in low-dose DCB group difference -1.6% (lower bound of the 90% two-sided CI -6.5%); Pnon-inferiority < 0.01. Overall death rate was low (2.0%) and no major amputation occurred.
Two DCBs with different coating characteristics exhibited comparable results with excellent effectiveness and safety through 12 months for femoropopliteal interventions including a wide range of lesion lengths.
The trial is registered with ClinicalTrials.gov (NCT02701543).
Missense mutations in the human secretary carrier-associated membrane protein 5 (SCAMP5) cause a variety of neurological disorders including neurodevelopmental delay, epilepsy, and Parkinson's ...disease. We recently documented the importance of SCAMP2 in the regulation of T-type calcium channel expression in the plasma membrane. Here, we show that similar to SCAMP2, the co-expression of SCAMP5 in tsA-201 cells expressing recombinant Ca
3.1, Ca
3.2, and Ca
3.3 channels nearly abolished whole-cell T-type currents. Recording of intramembrane charge movements revealed that SCAMP5-induced inhibition of T-type currents is primarily caused by the reduced expression of functional channels in the plasma membrane. Moreover, we show that SCAMP5-mediated downregulation of Ca
3.2 channels is essentially preserved with disease-causing SCAMP5 R91W and G180W mutations. Hence, this study extends our previous findings with SCAMP2 and indicates that SCAMP5 also contributes to repressing the expression of T-type channels in the plasma membrane.
Described by the Belgian cytologist Christian De Duve in 1949,
1
lysosomes (from the Greek "digestive bodies") are ubiquitous specialized intracellular organelles that ensure the ...degradation/recycling of macromolecules (proteins, lipids, membranes) through the activity of specific enzymes (i.e., acid hydrolases). They receive their substrates through different internalization pathways (i.e., endocytosis, phagocytosis and autophagy) and are involved in a wide range of physiological functions from cell death and signaling to cholesterol homeostasis and plasma membrane repair.
2
In Mammals, 50 soluble lysosomal hydrolases have been described, each targeting specific substrates. They are confined in the lumen of the lysosome and require an optimum pH (i.e., pH 4.5) to work. This acidic pH compared with the slightly alkaline pH of the cytosol (i.e., ~pH 7.2) is maintained by the activity of integral lysosomal membrane proteins (LMPs, that represent the second class of lysosomal proteins), including the V-type proton (H
+
)-ATPase
3
and the chloride ion channel CLC7
4
that pumps protons from the cytosol across the lysosomal membrane.
Background Peripheral arterial disease (PAD) is one of the most underestimated diseases because of its high prevalence and unfavorable prognosis. Many PAD patients without suitable autologous veins ...or options for endovascular treatment receive prosthetic above-knee femoropopliteal bypass (PAKB). Until now predictors of prosthetic bypass failure and of increased amputation risk remain indistinct. This study aimed to identify predictive factors associated with better bypass patency and limb salvage to achieve a more favorable outcome after PAKB reconstruction. Methods Pre-, intra-, and postoperative data of 244 PAKB procedures performed at a German university medical center were collected and analyzed using univariate and multivariate methods. To our knowledge this 12-year experience is the largest retrospective study to identify predictors for patency and limb salvage after PAKB reconstruction. Results Of the PAD patients 94% (229/244) were followed for an average of 34.9 months. Patient cohorts characteristics were: mean age, 66.1 years, 181 men (74%), claudication (64%), rest pain (16%), ischemic lesions (20%), arterial hypertension (92%), smoking (79%), hyperlipidemia (65%) and type 2 diabetes (43%). Cumulative primary 1- and 3-year graft patency rates were 60.8% and 50.7%, respectively, and cumulative 1- and 3-year limb salvage rates were 89.3% and 86.1%, respectively. One hundred seven bypasses (43.9%) failed, 26 patients (10.7%) required a major and seven patients (2.9%) required a minor amputation. Overall survival rates of PAD patients after 1- and 3-years were 94.4% and 82.9%, respectively. Subjective symptom improvement was found to be the most important prognostic follow-up factor for graft patency and limb salvage. Patients with recurrent symptoms in the follow-up had an increased risk of emerging bypass failure compared with patients with subjective symptom improvement (patency at 1 year: 40.8% vs 100% and at 3 years: 26% vs 100%; P < .001). No patient with subjective improvement in symptoms during follow-up underwent an amputation (limb salvage at 1 year: 100% vs 79% and at 3 years: 100% vs 72.8%; P < .001). Therefore, subjective symptom improvement should be the decisive criterion to determine follow-up intervals of PAD patients. In univariate analysis further significant factors associated with better graft patency and limb salvage rates were: claudication compared with critical ischemia, larger graft diameter (>6 mm), pre- and postoperative antiplatelet therapy, statin therapy independent from lipid values after PAKB revascularization, and an experienced vascular surgeon. Conclusions In our study, we determined the subjective improvement in symptoms as the most important prognostic factor for bypass function and limb salvage after PAKB. Furthermore, disease stage of critical ischemia, graft diameter, preoperative aspirin use, and postoperative statin medication were independent predictive factors. Therefore, PAD patients should be treated with aspirin pre- and postoperatively as well as with a statin postoperatively. In case of PAKB reconstruction only prostheses with a large diameter ( > 6 mm) should be used and the procedure should be performed by an experienced surgeon. Considering these results with regard to the predictive factors for better graft patency and limb salvage rates a significant more favorable outcome during the follow-up and an increased 5-year patency rate for PAKB reconstructions can be expected.
Abstract
Voltage-gated calcium channels are essential regulators of brain function where they support depolarization-induced calcium entry into neurons. They consist of a pore-forming subunit (Ca
v
α
...1
) that requires co-assembly with ancillary subunits to ensure proper functioning of the channel. Among these ancillary subunits, the Ca
v
β plays an essential role in regulating surface expression and gating of the channels. This regulation requires the direct binding of Ca
v
β onto Ca
v
α
1
and is mediated by the alpha interacting domain (AID) within the Ca
v
α
1
subunit and the α binding pocket (ABP) within the Ca
v
β subunit. However, additional interactions between Ca
v
α
1
and Ca
v
β have been proposed. In this study, we analyzed the importance of Ca
v
β
3
surface charged residues in the regulation of Ca
v
2.1 channels. Using alanine-scanning mutagenesis combined with electrophysiological recordings we identified several amino acids within the Ca
v
β
3
subunit that contribute to the gating of the channel. These findings add to the notion that additional contacts besides the main AID/ABP interaction may occur to fine-tune the expression and properties of the channel.
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