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Endothelial dysfunction is a major player in the development and progression of vascular pathology in pulmonary arterial hypertension (PAH), a disease associated with small vessel loss and obstructive vasculopathy that leads to increased pulmonary vascular resistance, subsequent right heart failure, and premature death. Over the past ten years, there has been tremendous progress in our understanding of pulmonary endothelial biology as it pertains to the genetic and molecular mechanisms that orchestrate the endothelial response to direct or indirect injury, and how their dysregulation can contribute to the pathogenesis of PAH. As one of the major topics included in the 2017 Grover Conference Series, discussion centered on recent developments in four areas of pulmonary endothelial biology: (1) angiogenesis; (2) endothelial-mesenchymal transition (EndMT); (3) epigenetics; and (4) biology of voltage-gated ion channels. The present review will summarize the content of these discussions and provide a perspective on the most promising aspects of endothelial dysfunction that may be amenable for therapeutic development.

Muscle spindles encode mechanosensory information by mechanisms that remain only partially understood. Their complexity is expressed in mounting evidence of various molecular mechanisms that play essential roles in muscle mechanics, mechanotransduction and intrinsic modulation of muscle spindle firing behaviour. Biophysical modelling provides a tractable approach to achieve more comprehensive mechanistic understanding of such complex systems that would be difficult/impossible by more traditional, reductionist means. Our objective here was to construct the first integrative biophysical model of muscle spindle firing. We leveraged current knowledge of muscle spindle neuroanatomy and in vivo electrophysiology to develop and validate a biophysical model that reproduces key in vivo muscle spindle encoding characteristics. Crucially, to our knowledge, this is the first computational model of mammalian muscle spindle that integrates the asymmetric distribution of known voltage‐gated ion channels (VGCs) with neuronal architecture to generate realistic firing profiles, both of which seem likely to be of great biophysical importance. Results predict that particular features of neuronal architecture regulate specific characteristics of Ia encoding. Computational simulations also predict that the asymmetric distribution and ratios of VGCs is a complementary and, in some instances, orthogonal means to regulate Ia encoding. These results generate testable hypotheses and highlight the integral role of peripheral neuronal structure and ion channel composition and distribution in somatosensory signalling. What is the central question of the study? How does the neuronal architecture and asymmetric distribution of voltage‐gated channels influence mechanosensory encoding by muscle spindle afferents? What is the main finding and its importance? The results predict that neuronal architecture and the distribution and ratios of voltage‐gated ion channels are a complementary and, in some instances, orthogonal means to regulate Ia encoding. The importance of these findings highlights the integral role of peripheral neuronal structure and ion channel expression in mechanosensory signalling. Generally, our computational approach offers an integrative means to generate testable hypotheses and prioritize targets for future mechanistic studies.

Tiagabine is an antiepileptic drug used for the treatment of partial seizures in humans. Recently, this drug has been found useful in several non-epileptic conditions, including anxiety, chronic pain and sleep disorders. Since tachycardia—an impairment of cardiac rhythm due to cardiac ion channel dysfunction—is one of the most commonly reported non-neurological adverse effects of this drug, in the present paper we have undertaken pharmacological and numerical studies to assess a potential cardiovascular risk associated with the use of tiagabine. A chemical interaction of tiagabine with a model of human voltage-gated ion channels (VGICs) is described using the molecular docking method. The obtained in silico results imply that the adverse effects reported so far in the clinical cardiological of tiagabine could not be directly attributed to its interactions with VGICs. This is also confirmed by the results from the isolated organ studies (i.e., calcium entry blocking properties test) and in vivo (electrocardiogram study) assays of the present research. It was found that tachycardia and other tiagabine-induced cardiac complications are not due to a direct effect of this drug on ventricular depolarization and repolarization.

Patients with small fiber neuropathy (SFN) suffer from neuropathic pain, which is still a therapeutic problem. Changed activation patterns of mechano-insensitive peripheral nerve fibers (CMi) could cause neuropathic pain. However, there is sparse knowledge about mechanisms leading to CMi dysfunction since it is difficult to dissect specific molecular mechanisms in humans. We used an model to elucidate molecular causes of CMi dysfunction as observed in single nerve fiber recordings (microneurography) of SFN patients. We analyzed microneurography data from 97 CMi-fibers from healthy individuals and 34 of SFN patients to identify activity-dependent changes in conduction velocity. Using the NEURON environment, we adapted a biophysical realistic preexisting CMi-fiber model with ion channels described by Hodgkin-Huxley dynamics for identifying molecular mechanisms leading to those changes. Via a grid search optimization, we assessed the interplay between different ion channels, Na-K-pump, and resting membrane potential. Changing a single ion channel conductance, Na-K-pump or membrane potential individually is not sufficient to reproduce in-silico CMi-fiber dysfunction of unchanged activity-dependent conduction velocity slowing and quicker normalization of conduction velocity after stimulation as observed in microneurography. We identified the best combination of mechanisms: increased conductance of potassium delayed-rectifier and decreased conductance of Na-K-pump and depolarized membrane potential. When the membrane potential is unchanged, opposite changes in Na-K-pump and ion channels generate the same effect. Our study suggests that not one single mechanism accounts for pain-relevant changes in CMi-fibers, but a combination of mechanisms. A depolarized membrane potential, as previously observed in patients with neuropathic pain, leads to changes in the contribution of ion channels and the Na-K-pump. Thus, when searching for targets for the treatment of neuropathic pain, combinations of several molecules in interplay with the membrane potential should be regarded.

Storage and periodic expulsion of urine is regulated by a neural control system in the brain and spinal cord that coordinates the reciprocal activity of two functional units in the lower urinary tract (LUT): (a) a reservoir (the urinary bladder) and (b) an outlet (bladder neck, urethra and striated muscles of the urethral sphincter). Control of the bladder and urethral outlet is dependent on three sets of peripheral nerves: parasympathetic, sympathetic and somatic nerves that contain afferent as well as efferent pathways. Afferent neurons innervating the bladder have A‐δ or C‐fibre axons. Urine storage reflexes are organized in the spinal cord, whereas voiding reflexes are mediated by a spinobulbospinal pathway passing through a coordination centre (the pontine micturition centre) located in the brainstem. Storage and voiding reflexes are activated by mechanosensitive A‐δ afferents that respond to bladder distension. Many neurotransmitters including acetylcholine, norepinephrine, dopamine, serotonin, excitatory and inhibitory amino acids, adenosine triphosphate, nitric oxide and neuropeptides are involved in the neural control of the LUT. Injuries or diseases of the nervous system as well as disorders of the peripheral organs can produce LUT dysfunctions including: (1) urinary frequency, urgency and incontinence or (2) inefficient voiding and urinary retention. Neurogenic detrusor overactivity is triggered by C‐fibre bladder afferent axons, many of which terminate in the close proximity to the urothelium. The urothelial cells exhibit ‘neuron‐like’ properties that allow them to respond to mechanical and chemical stimuli and to release transmitters that can modulate the activity of afferent nerves. British Journal of Pharmacology (2006) 147, S25–S40. doi:10.1038/sj.bjp.0706604

Drug studies targeting neuronal ion channels are crucial to understand neuronal function and develop therapies for neurological diseases. The traditional method to study neuronal ion‐channel activities heavily relies on the whole‐cell patch clamp as the industry standard. However, this technique is both technically challenging and labour‐intensive, while involving the complexity of keeping cells alive with low throughput. Therefore, the shortcomings are limiting the efficiency of ion‐channel‐related neuroscience research and drug testing. Here, this work reports a new system of integrating neuron membranes with organic microelectrode arrays (OMEAs) for ion‐channel‐related drug studies. This work demonstrates that the supported lipid bilayers (SLBs) derived from both neuron‐like (neuroblastoma) cells and primary neurons are integrated with OMEAs for the first time. The increased expression of voltage‐gated calcium (CaV) ion channels on differentiated SH‐SY5Y SLBs  compared to non‐differentiated ones is sensed electrically. Also, dose‐response of the CaV ion‐channel blocking effect on primary cortical neuronal SLBs from rats is monitored. The dose range causing ion channel blocking is comparable to literature. This system overcomes the major challenges from traditional methods (e.g., patch clamp) and showcases an easy‐to‐test, rapid, ultra‐sensitive, cell‐free, and high‐throughput platform to monitor dose‐dependent ion‐channel blocking effects on native neuronal membranes. Primary neuron membranes can be isolated and integrated with microelectrode arrays. This is a study using electrochemical impedance spectroscopy for monitoring the neuronal membrane quality and detecting ion channel blockage on the neuron membranes, which could be a novel technique for drug screening and neuroscience research.

Emerging human induced pluripotent stem cells (hiPSCs)‐based neuronal models are useful for studying human neural development. However, existing protocols for differentiating neurons from hiPSCs generally require extended timeframes, making it difficult to capture the rapid, early stages of neuronal morphogenesis and functional maturation. This study presents an in vitro human neuronal model derived from hiPSCs with rapid morphological and functional maturity, by using the combined small molecules and proteins (SMP) protocol. This SMP‐induced, hiPSC‐derived neuronal model recapitulates core aspects of human neuronal development, providing a temporally compressed system for studying early neuronal development. On the basis of this model, this study demonstrates that both Cav1.2 and Cav1.3, the two subtypes of L‐type voltage‐gated calcium channels that mediate calcium ion influx, are essential for early morphogenesis of human neuronal development. Moreover, ECEL1 (endothelin converting enzyme‐like 1) is identified as a key regulator of human neuronal functional developmental maturation in the early stage of SMP‐induced hiPSCs differentiation. ECEL1 acts through calmodulin 3 (CALM3) to regulate functional assembly and expression of multiple ion channels (e.g., voltage‐gated sodium ion channels) in neuronal functional development and maturation. These findings illuminate novel mechanisms underlying the morphogenesis and functional maturation of human neurons that are involved in human brain development. Using human induced pluripotent stem cells (hiPSCs)‐derived neuronal model, Tian and colleagues reveal that voltage‐gated calcium channels Cav1.2 and Cav1.3, and their mediated calcium ion influx, are essential for early morphogenesis of human neuronal development, while ECEL1 underlies human neuronal functional developmental maturation through CALM3‐mediated ion channels assembly in neuronal functional development.

L‐type voltage‐gated calcium ion channels (L‐VGCCs) have been demonstrated to be the mediator of several significant intracellular activities in excitable cells, such as neurons, chromaffin cells and myocytes. Recently, an increasing number of studies have investigated the function of L‐VGCCs in non‐excitable cells, particularly stem cells. However, there appear to be no systematic reviews of the relationship between L‐VGCCs and stem cells, and filling this gap is prescient considering the contribution of L‐VGCCs to the proliferation and differentiation of several types of stem cells. This review will discuss the possible involvement of L‐VGCCs in stem cells, mainly focusing on osteogenesis mediated by mesenchymal stem cells (MSCs) from different tissues and neurogenesis mediated by neural stem/progenitor cells (NSCs). Additionally, advanced applications that use these channels as the target for tissue engineering, which may offer the hope of tissue regeneration in the future, will also be explored.

Homeostatic plasticity occurs through diverse cellular and synaptic mechanisms, and extensive investigations over the preceding decade have established Kv2.1 ion channels as key homeostatic regulatory elements in several central neuronal systems. As in these cellular systems, Kv2.1 channels in spinal motoneurons (MNs) localize within large somatic membrane clusters. However, their role in regulating motoneuron activity is not fully established in vivo. We have previously demonstrated marked Kv2.1 channel redistribution in MNs following in vitro glutamate application and in vivo peripheral nerve injury (Romer et al., 2014, Brain Research, 1547:1–15). Here, we extend these findings through the novel use of a fully intact, in vivo rat preparation to show that Kv2.1 ion channels in lumbar MNs rapidly and reversibly redistribute throughout the somatic membrane following 10 min of electrophysiological sensory and/or motor nerve stimulation. These data establish that Kv2.1 channels are remarkably responsive in vivo to electrically evoked and synaptically driven action potentials in MNs, and strongly implicate motoneuron Kv2.1 channels in the rapid homeostatic response to altered neuronal activity. Delayed rectifier Kv2.1 ion channels are key homeostatic regulatory elements in several neuronal systems, but the functional implications of large Kv2.1 channel clusters in spinal motoneurons (MNs) are not well established. Here, for the first time, we demonstrate that both motor and sensory nerve activity rapidly influence Kv2.1 clustering in spinal MNs in vivo and suggest that Kv2.1 channels contribute to the homeostatic regulation of motoneuron firing properties. These data provide important mechanistic insight into the prominent and puzzling Kv2.1 cluster dynamics that have been observed in spinal MNs.

Neuropathic pain is a chronic and debilitating disorder of the somatosensory system that affects a significant proportion of the population and is characterized by abnormal responses such as hyperalgesia and allodynia. Voltage-gated ion channels, including sodium (NaV), calcium (CaV), and potassium (KV) channels, play a pivotal role in modulating neuronal excitability and pain signal transmission following nerve injury. This review intends to provide a comprehensive analysis of the molecular and cellular mechanisms by which dysregulation in the expression, localization, and function of specific NaV channel subtypes (mainly NaV1.7 and NaV1.8) and their auxiliary subunits contributes to aberrant neuronal activation, the generation of ectopic discharges, and sensitization in neuropathic pain. Likewise, special emphasis is placed on the crucial role of CaV channels, particularly CaV2.2 and the auxiliary subunit CaVα2δ, whose overexpression increases calcium influx, neurotransmitter release, and neuronal hyperexcitability, thus maintaining persistent pain states. Furthermore, KV channels (particularly KV7 channels) function as brakes on neuronal excitability, and their dysregulation facilitates the development and maintenance of neuropathic pain. Therefore, targeting specific KV channel subtypes to restore their function is also a promising therapeutic strategy for alleviating neuropathic pain symptoms. On the other hand, recent advances in the development of small molecules as selective modulators or inhibitors targeting voltage-gated ion channels are also discussed. These agents have improved efficacy and safety profiles in preclinical and clinical studies by attenuating pathophysiological channel activity and restoring neuronal function. This review seeks to contribute to guiding future research and drug development toward more effective mechanism-based treatments by discussing the molecular mechanisms underlying neuropathic pain and highlighting translational therapeutic opportunities.