Biology subjects

Ruben, P. C.

Publications and source records attributed to Ruben, P. C..

3 recordsLinked to original sources

bioRxiv2023

Molecular pharmacology of selective NaV1.6 and dual NaV1.6 and NaV1.2 channel inhibitors that suppress excitatory neuronal activity ex vivo

Sodium channel inhibitors are used to treat neurological disorders of hyperexcitability. However, all currently available sodium channel targeting anti-seizure medications are non-selective among the NaV isoforms which potentially limits efficacy and therapeutic safety margins. XPC-7724 and XPC-5462 represent a new class of small molecule compounds. These compounds target inhibition of the NaV1.6 and NaV1.2 channels in excitatory pyramidal neurons and possess a molecular selectivity of >100 fold against NaV1.1 channels that are dominant in inhibitory cells. This profile will enable pharmacological dissection of the physiological roles of NaV1.2 and NaV1.6 and help to define the role of each channel in disease states. These compounds bind to and stabilize the inactivated-state of the channels, demonstrate higher potency with longer residency times, and slower off-rates than carbamazepine and phenytoin. These compounds possess cellular selectivity ex vivo in inhibiting action potential firing in cortical excitatory pyramidal neurons, whilst sparing fast spiking inhibitory interneurons. XPC-5462 also suppresses epileptiform activity in an ex vivo brain slice seizure model. This class of compounds provides a unique approach for treating neuronal excitability disorders by selectively down-regulating excitatory circuits. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=194 HEIGHT=200 SRC="FIGDIR/small/551643v2_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@70750corg.highwire.dtl.DTLVardef@114756aorg.highwire.dtl.DTLVardef@289009org.highwire.dtl.DTLVardef@1086e23_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2020

Protein kinases mediate anti-inflammatory effects of cannabidiol and estradiol against high glucose in cardiac sodium channels

Background and purposeCardiovascular anomalies are predisposing factors for diabetes-induced morbidity and mortality. Recently, we showed that high glucose induces changes in the biophysical properties of Nav1.5 that could be strongly correlated to diabetes-induced arrhythmia. However, the mechanisms underlying hyperglycemia-induced inflammation, and how inflammation provokes cardiac arrhythmia, are not well understood. We hypothesized that inflammation could mediate the high glucose-induced biophyscial changes on Nav1.5 through protein phosphorylation by protein kinases A and C. We also hypothesized that this signaling pathway is, at least partly, involved in the cardiprotective effects of CBD and E2. Experimental approachTo test these ideas, we used Chinese hamster ovarian (CHO) cells transiently co-transfected with cDNA encoding human Nav1.5 -subunit under control, a cocktail of inflammatory mediators or 100 mM glucose conditions (for 24 hours). We used electrophysiological experiments and action potential modelling. Key ResultsInflammatory mediators, similar to 100 mM glucose, right shifted the voltage dependence of conductance and steady state fast inactivation and increased persistent current leading to computational prolongation of action potential (hyperexcitability) which could result in long QT3 arrhythmia. In addition, activators of PK-A or PK-C replicated the inflammation-induced gating changes of Nav1.5. Inhibitors of PK-A or PK-C, CBD or E2 mitigated all the potentially deleterious effects provoked by high glucose/inflammation. Conclusions and implicationsThese findings suggest that PK-A and PK-C may mediate the anti-inflammatory effects of CBD and E2 against high glucose-induced arrhythmia. CBD, via Nav1.5, may be a cardioprotective therapeutic approach in diabetic postmenopausal population. Bullet pointsWhat is already known: O_LIArrhythmias are among the common cardiac causes of morbidity and mortality in diabetes-related hyperglycemia. C_LIO_LIOne of the diabetes-induced arrhythmias is long-QT syndrome, caused by gating defects in the cardiac voltage-gated sodium channel (Nav1.5). C_LI What this study adds: O_LIInflammation and subsequent activation of PK-A and PK-C mediate the high glucose-induced electrophysiological changes of Nav1.5 in a manner consistent with the gating defects that underlie long-QT arrhythmia. C_LIO_LICannabidiol and estradiol rescue the high glucose induced Nav1.5 gating defects through, at least partly, this signaling pathway. C_LI Clinical significance: O_LIInflammation/PK-A and PK-C signaling pathway could be a potential therapeutic target to prevent arrhythmias associated with diabetes. C_LIO_LICannabidiol may be a therapeutic approach to prevent cardiac complications in diabetes, especially in postmenopausal populations due to the decreased levels of the cardioprotective estrogen. C_LI

pharmacology and toxicology↗

bioRxiv2017

A Mixed Periodic Paralysis & Myotonia Mutant, P1158S, Imparts pH Sensitivity in Skeletal Muscle Voltage-gated Sodium Channels

Skeletal muscle channelopathies, many of which are inherited as autosomal dominant mutations, include both myotonia and periodic paralysis. Myotonia is defined by a delayed relaxation after muscular contraction, whereas periodic paralysis is defined by episodic attacks of weakness. One sub-type of periodic paralysis, known as hypokalemic periodic paralysis (hypoPP), is associated with low potassium levels. Interestingly, the P1158S missense mutant, located in the third domain S4-S5 linker of the skeletal muscle voltage-gated sodium channel, Nav1.4, has been implicated in causing both myotonia and hypoPP. A common trigger for these conditions is physical activity. We previously reported that Nav1.4 is relatively insensitive to changes in extracellular pH compared to Nav1.2 and Nav1.5. Given that intense exercise is often accompanied by blood acidosis, we decided to test whether changes in pH would push gating in P1158S towards either phenotype. Our results indicate that, unlike in WT Nav1.4, low pH depolarizes the voltage-dependence of activation and steady-state fast inactivation, decreases current density, and increases late currents in P1185S. Thus, P1185S turns the normally pH-insensitive Nav1.4 into a proton-sensitive channel. Using action potential modeling we also predict a pH-to-phenotype correlation in patients with P1158S. We conclude that activities which alter blood pH may trigger myotonia or periodic paralysis in P1158S patients.\n\nSIGNIFICANCE STATEMENTVoltage-gated sodium channels (Nav) contribute to the physiology and pathophysiology of electrical signaling in excitable cells. Nav subtypes are expressed in a tissue-specific manner, thus they respond differently to physiological modulators. For instance, the cardiac subtype, Nav1.5, can be modified by changes in blood pH; however, the skeletal muscle subtype, Nav1.4, is mostly pH-insensitive. Nav1.4 mutants can mostly cause either hyper-or hypo-excitability in skeletal muscles, leading to conditions such as myotonia or periodic paralysis. P1158S uniquely causes both phenotypes. This study investigates pH-sensitivity in P1158S, and describes how physiological pH changes can push P1158S to cause myotonia and periodic paralysis.

biophysics↗