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"Huang, Christopher L.-H"
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Nerve and muscle
\"Written with undergraduate students in mind, the new edition of this classic textbook provides a compact introduction to the physiology of nerve and muscle. It gives a straightforward account of the fundamentals accompanied by some of the experimental evidence upon which this understanding is based. It first explores the nature of nerve impulses, clarifying their mechanisms in terms of ion flow through molecular channels in cell membranes. There then follows an account of the synaptic transmission processes by which one excitable cell influences activity in another. Finally, the emphasis turns to the consequences of excitable activity in the activation of contraction in skeletal, cardiac and smooth muscle, highlighting the relationships between cellular structure and function. This fourth edition includes new material on the molecular nature of ion channels, the activation of skeletal muscle and the function of cardiac and smooth muscle, reflecting exciting new developments in these rapidly growing fields\"-- Provided by publisher.
Book
Voltage-gated sodium channels in cancers
Voltage-gated sodium channels (VGSCs) initiate action potentials in electrically excitable cells and tissues. Surprisingly, some VGSC genes are aberrantly expressed in a variety of cancers, derived from “non-excitable” tissues that do not generate classic action potentials, showing potential as a promising pharmacological target for cancer. Most of the previous review articles on this topic are limited in scope, and largely unable to provide researchers with a comprehensive understanding of the role of VGSC in cancers. Here, we review the expression patterns of all nine VGSC α-subunit genes (SCN1A-11A) and their four regulatory β-subunit genes (SCN1B-4B). We reviewed data from the Cancer Genome Atlas (TCGA) database, complemented by an extensive search of the published papers. We summarized and reviewed previous independent studies and analyzed the VGSC genes in the TCGA database regarding the potential impact of VGSC on cancers. A comparison between evidence gathered from independent studies and data review was performed to scrutinize potential biases in prior research and provide insights into future research directions. The review supports the view that VGSCs play an important role in diagnostics as well as therapeutics of some cancer types, such as breast, colon, prostate, and lung cancer. This paper provides an overview of the current knowledge on voltage-gated sodium channels in cancer, as well as potential avenues for further research. While further research is required to fully understand the role of VGSCs in cancer, the potential of VGSCs for clinical diagnosis and treatment is promising.
Journal Article
البحث في الطب من تخطيط البحث إلى كتابة الرسالة
يهدف هذا الكتاب إلى وضع دليل إرشادي مبسط للبحث العلمي موجه للطلاب وممارسي الطب وهو يأخذ القارئ إلى كيفية عمل بحث علمي خطوة بخطوة من مرحلة إيجاد فكرة البحث والتخطيط لها إلى كتابة رالة البحث ونشرها في المجلات العلمية كذلك يتناول أهمية البحث العلمي وما يمكن أن يضيفه للمستقبل الوظيفي والشخصي للباحث، ويشرح الفروق بين الأنظمة التعليمية العالمية ومميزات كل نظام كما أنه يفصل مراحل البحث العلمي والإجراءات والخطوات المناسبة بما فيها طريقة البحث عن الأدبية المتعلقة بموضوع البحث وكتابة الورقة العملية أو الرسالة بطريقة مناسبة للنشر في المجلات العلمية وكذلك يقدم الكتاب نصائح في كيفية إعداد وتقديم العروض التقديمية في اللقاءات العلمي.
Book
Is the voltage-gated sodium channel β3 subunit (SCN3B) a biomarker for glioma?
Recent studies suggest a need for reliable biomarkers enhancing prognosis prediction and treatment strategies in cancer. Here, we performed a data analysis bearing on the expression of SCN3B, voltage-gated sodium channel (VGSC) β3 subunit, as a possible candidate for the development of a glioma biomarker for the first time. This extends our previous review article that mentioned the potential of SCN3B as a prognostic biomarker for glioma survival, further examining its association with existing indicators and immune responses. We utilized clinical and genomic data from multiple glioma cohorts. These include the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). We employed analytical techniques including time-dependent receiver operating characteristic (ROC) analysis, decision curves analysis (DCA), and correlation studies with immune checkpoint markers. Our findings indicate a differential SCN3B expression between glioma grades, and that this significantly correlates with patient survival, particularly in oligodendroglioma subtypes. The DCA curves suggested that the inclusion of SCN3B in the prognostic model would improve decision-making in these subtypes. Moreover, SCN3B expression positively correlated with the presence of key immune cells and negatively correlated with several immune checkpoint inhibitors. This suggests potential roles in modulating immune responses in glioma. Thus, SCN3B emerges as a promising potential prognostic biomarker for glioma, especially for oligodendroglioma. Its dual correlations with prognosis and immune regulation present a compelling case for further experimental and clinical investigations to establish its utility in enhancing glioma management strategies. These findings underscore the importance of integrating novel biomarkers with traditional prognostic models to refine treatment paradigms and improve patient outcomes.
Journal Article
Empagliflozin rescues pro-arrhythmic and Ca2+ homeostatic effects of transverse aortic constriction in intact murine hearts
We explored physiological effects of the sodium-glucose co-transporter-2 inhibitor empagliflozin on intact experimentally hypertrophic murine hearts following transverse aortic constriction (TAC). Postoperative drug (2–6 weeks) challenge resulted in reduced late Na
+
currents, and increased phosphorylated (p-)CaMK-II and Nav1.5 but not total (t)-CaMK-II, and Na
+
/Ca
2+
exchanger expression, confirming previous cardiomyocyte-level reports. It rescued TAC-induced reductions in echocardiographic ejection fraction and fractional shortening, and diastolic anterior and posterior wall thickening. Dual voltage- and Ca
2+
-optical mapping of Langendorff-perfused hearts demonstrated that empagliflozin rescued TAC-induced increases in action potential durations at 80% recovery (APD
80
), Ca
2+
transient peak signals and durations at 80% recovery (CaTD
80
), times to peak Ca
2+
(TTP
100
) and Ca
2+
decay constants (Decay
30–90
) during regular 10-Hz stimulation, and Ca
2+
transient alternans with shortening cycle length. Isoproterenol shortened APD
80
in sham-operated and TAC-only hearts, shortening CaTD
80
and Decay
30–90
but sparing TTP
100
and Ca
2+
transient alternans in all groups. All groups showed similar APD
80
, and TAC-only hearts showed greater CaTD
80
, heterogeneities following isoproterenol challenge. Empagliflozin abolished or reduced ventricular tachycardia and premature ventricular contractions and associated re-entrant conduction patterns, in isoproterenol-challenged TAC-operated hearts following successive burst pacing episodes. Empagliflozin thus rescues TAC-induced ventricular hypertrophy and systolic functional, Ca
2+
homeostatic, and pro-arrhythmogenic changes in intact hearts.
Journal Article
Sodium channel biophysics, late sodium current and genetic arrhythmic syndromes
Arrhythmias arise from breakdown of orderly action potential (AP) activation, propagation and recovery driven by interactive opening and closing of successive voltage-gated ion channels, in which one or more Na
+
current components play critical parts. Early peak, Na
+
currents (
I
Na
) reflecting channel
activation
drive the AP upstroke central to cellular activation and its propagation. Sustained late Na
+
currents (
I
Na-L
) include contributions from a component with a delayed
inactivation
timecourse influencing AP duration (APD) and refractoriness, potentially causing pro-arrhythmic phenotypes. The magnitude of
I
Na-L
can be analysed through overlaps or otherwise in the overall voltage dependences of the steady-state properties and kinetics of activation and inactivation of the Na
+
conductance. This was useful in analysing repetitive firing associated with paramyotonia congenita in skeletal muscle. Similarly, genetic cardiac Na
+
channel abnormalities increasing
I
Na-L
are implicated in triggering phenomena of automaticity, early and delayed afterdepolarisations and arrhythmic substrate. This review illustrates a wide range of situations that may accentuate
I
Na-L
. These include (1) overlaps between steady-state activation and inactivation increasing
window current
, (2) kinetic deficiencies in Na
+
channel inactivation leading to
bursting phenomena
associated with repetitive channel openings and (3)
non-equilibrium gating
processes causing channel re-opening due to more rapid recoveries from inactivation. All these biophysical possibilities were identified in a selection of abnormal human
SCN5A
genotypes. The latter presented as a broad range of clinical arrhythmic phenotypes, for which effective therapeutic intervention would require specific identification and targeting of the diverse electrophysiological abnormalities underlying their increased
I
Na-L
.
Journal Article
Sarcoplasmic reticular Ca2+-ATPase inhibition paradoxically upregulates murine skeletal muscle Nav1.4 function
Skeletal muscle Na
+
channels possess Ca
2+
- and calmodulin-binding sites implicated in Nav1.4 current (
I
Na
) downregulation following ryanodine receptor (RyR1) activation produced by exchange protein directly activated by cyclic AMP or caffeine challenge, effects abrogated by the RyR1-antagonist dantrolene which itself increased
I
Na
. These findings were attributed to actions of consequently altered cytosolic Ca
2+
, [Ca
2+
]
i
, on Na
v
1.4. We extend the latter hypothesis employing cyclopiazonic acid (CPA) challenge, which similarly increases [Ca
2+
]
i
, but through contrastingly inhibiting sarcoplasmic reticular (SR) Ca
2+
-ATPase. Loose patch clamping determined Na
+
current (
I
Na
) families in intact native murine gastrocnemius skeletal myocytes, minimising artefactual [Ca
2+
]
i
perturbations. A bespoke flow system permitted continuous
I
Na
comparisons through graded depolarizing steps in identical stable membrane patches before and following solution change. In contrast to the previous studies modifying RyR1 activity, and imposing control solution changes, CPA (0.1 and 1 µM) produced persistent increases in
I
Na
within 1–4 min of introduction. CPA pre-treatment additionally abrogated previously reported reductions in
I
Na
produced by 0.5 mM caffeine. Plots of peak current against voltage excursion demonstrated that 1 µM CPA increased maximum
I
Na
by ~ 30%. It only slightly decreased half-maximal activating voltages (
V
0.5
) and steepness factors (
k
), by 2 mV and 0.7, in contrast to the
V
0.5
and
k
shifts reported with direct RyR1 modification. These paradoxical findings complement previously reported downregulatory effects on Nav1.4 of RyR1-agonist mediated
increases
in
bulk
cytosolic [Ca
2+
]. They implicate possible
local
tubule-sarcoplasmic triadic domains containing
reduced
[Ca
2+
]
TSR
in the observed upregulation of Nav1.4 function following CPA-induced SR Ca
2+
depletion.
Journal Article
Finite element analysis predicts Ca2+ microdomains within tubular-sarcoplasmic reticular junctions of amphibian skeletal muscle
A finite element analysis modelled diffusional generation of steady-state Ca
2+
microdomains within skeletal muscle transverse (T)-tubular-sarcoplasmic reticular (SR) junctions, sites of ryanodine receptor (RyR)-mediated SR Ca
2+
release. It used established quantifications of sarcomere and T-SR anatomy (radial diameter
d
=
220
n
m
; axial distance
w
=
12
n
m
). Its boundary SR Ca
2+
influx densities,
J
influx
, reflected step impositions of
influxes
,
Φ
influx
=
J
influx
π
d
2
4
,
deduced from previously measured Ca
2+
signals following muscle fibre depolarization.
Predicted
steady-state T-SR junctional edge [Ca
2+
], [Ca
2+
]
edge,
matched reported corresponding
experimental
cytosolic [Ca
2+
] elevations given diffusional boundary
efflux
Φ
efflux
=
D
[
Ca
2
+
]
edge
λ
(
π
dw
)
,
established cytosolic Ca
2+
diffusion coefficients
(
D
=
4
×
10
7
nm
2
/
s
)
and exit length
λ
=
9.2
n
m
. Dependences of
predicted
[Ca
2+
]
edge
upon
J
influx
then matched those of
experimental
[Ca
2+
] upon Ca
2+
release through their entire test voltage range. The resulting model consistently predicted elevated steady-state T-SR junctional ~ µM-[Ca
2+
] elevations radially declining from maxima at the T-SR junction centre along the entire axial T-SR distance. These [Ca
2+
] heterogeneities persisted through 10
4
- and fivefold, variations in
D
and
w
around, and fivefold reductions in
d
below, control values, and through reported resting muscle cytosolic [Ca
2+
] values, whilst preserving the flux conservation (
Φ
influx
=
Φ
efflux
)
condition,
C
a
2
+
edge
=
λ
dJ
influx
4
D
w
. Skeletal muscle thus potentially forms physiologically significant ~ µM-[Ca
2+
] T-SR microdomains that could regulate cytosolic and membrane signalling molecules including calmodulin and RyR, These findings directly fulfil recent experimental predictions invoking such Ca
2+
microdomains in observed regulatory effects upon Na
+
channel function, in a mechanism potentially occurring in similar restricted intracellular spaces in other cell types.
Journal Article
Veratridine-Induced Oscillations in Nav 1.7 but Not Nav 1.5 Sodium Channels Are Revealed by Membrane Potential Sensitive Dye
Voltage-gated sodium channels (Navs) are critical for membrane potential depolarisation in cells, with especially important roles in neuronal and cardiomyocyte membranes. Their malfunction results in a range of disorders, and they are the target of many widely used drugs. A rapid yet accurate functional assay is therefore desirable both to probe for novel active compounds and to better understand the many different Nav isoforms. Here, we use fluorescence to monitor Nav function: cells expressing either the cardiac Nav 1.5 or pain-associated Nav 1.7 were loaded with fluorescent membrane potential sensitive dye and then stimulated with veratridine. Cells expressing Nav 1.5 show a concentration-dependent slow rise and then a plateau in fluorescence. In contrast, cells expressing Nav 1.7 show a more rapid rise and then unexpected oscillatory behavior. Inhibition by flecainide and mexiletine demonstrates that these oscillations are Nav-dependent. Thus, we show that this fluorescent membrane potential dye can provide useful functional data and that we can readily distinguish between these two Nav isoforms because of the behavior of cells expressing them when activated by veratridine. We consider these distinct behaviors may be due to different interactions of veratridine with the different Nav isoforms, although more studies are needed to understand the mechanism underlying the oscillations.
Journal Article
Can the SARS-CoV-2 Spike Protein Bind Integrins Independent of the RGD Sequence?
The RGD motif in the Severe Acute Syndrome Coronavirus 2 (SARS-CoV-2) spike protein has been predicted to bind RGD-recognizing integrins. Recent studies have shown that the spike protein does, indeed, interact with α V β 3 and α 5 β 1 integrins, both of which bind to RGD-containing ligands. However, computational studies have suggested that binding between the spike RGD motif and integrins is not favourable, even when unfolding occurs after conformational changes induced by binding to the canonical host entry receptor, angiotensin-converting enzyme 2 (ACE2). Furthermore, non-RGD-binding integrins, such as α x , have been suggested to interact with the SARS-CoV-2 spike protein. Other viral pathogens, such as rotaviruses, have been recorded to bind integrins in an RGD-independent manner to initiate host cell entry. Thus, in order to consider the potential for the SARS-CoV-2 spike protein to bind integrins independent of the RGD sequence, we investigate several factors related to the involvement of integrins in SARS-CoV-2 infection. First, we review changes in integrin expression during SARS-CoV-2 infection to identify which integrins might be of interest. Then, all known non-RGD integrin-binding motifs are collected and mapped to the spike protein receptor-binding domain and analyzed for their 3D availability. Several integrin-binding motifs are shown to exhibit high sequence similarity with solvent accessible regions of the spike receptor-binding domain. Comparisons of these motifs with other betacoronavirus spike proteins, such as SARS-CoV and RaTG13, reveal that some have recently evolved while others are more conserved throughout phylogenetically similar betacoronaviruses. Interestingly, all of the potential integrin-binding motifs, including the RGD sequence, are conserved in one of the known pangolin coronavirus strains. Of note, the most recently recorded mutations in the spike protein receptor-binding domain were found outside of the putative integrin-binding sequences, although several mutations formed inside and close to one motif, in particular, may potentially enhance binding. These data suggest that the SARS-CoV-2 spike protein may interact with integrins independent of the RGD sequence and may help further explain how SARS-CoV-2 and other viruses can evolve to bind to integrins.
Journal Article