Activation of SGK1.1 Upregulates the M-current in the Presence of Epilepsy Mutations

In the central nervous system, the M-current plays a critical role in regulating subthreshold electrical excitability of neurons, determining their firing properties and responsiveness to synaptic input. The M-channel is mainly formed by subunits Kv7.2 and Kv7.3 that co-assemble to form a heterotetrametric channel. Mutations in Kv7.2 and Kv7.3 are associated with hyperexcitability phenotypes including benign familial neonatal epilepsy (BFNE) and neonatal epileptic encephalopathy (NEE). SGK1.1, the neuronal isoform of the serum and glucocorticoids-regulated kinase 1 (SGK1), increases M-current density in neurons, leading to reduced excitability and protection against seizures. Herein, using two-electrode voltage clamp on Xenopus laevis oocytes, we demonstrate that SGK1.1 selectively activates heteromeric Kv7 subunit combinations underlying the M-current. Importantly, activated SGK1.1 increases M-channel activity in the presence of two different epilepsy mutations found in Kv7.2, R207W and A306T. In addition, proximity ligation assays in the N2a cell line allowed us to address the effect of these mutations on Kv7-SGK1.1-Nedd4 molecular associations, a proposed pathway underlying augmentation of M-channel activity by SGK1.1

Gating of Ion Channels

Excitable cells, such as neurons and muscles, use ion channels to generate electrical and chemical signals that underlie their functions. Examples include the electrical signals underlying the complex neuronal circuitry in the brain, the secretion of hormones and neurotransmitters, skeletal and cardiac muscle contraction, and the signaling events that lead to fertility. Because of their pivotal role in cellular signaling and electrical excitability, a major goal in modern biology has been to determine the physical properties that control and modulate ion channel function. This chapter briefly reviews classical works about the gating of ion channels. Furthermore, it discusses some innovative approaches that when combined with biophysical and mathematical simulations have contributed to the current understanding of channel gating.

Ion Channel Function and Electrical Excitability in the Zona Glomerulosa: A Network Perspective on Aldosterone Regulation

Aldosterone excess is a pathogenic factor in many hypertensive disorders. The discovery of numerous somatic and germline mutations in ion channels in primary hyperaldosteronism underscores the importance of plasma membrane conductances in determining the activation-state of zona glomerulosa (zG) cells. Electrophysiological recordings describe an electrically quiescent behavior for dispersed zG cells. Yet, emerging data indicate that in native rosette structures in situ, zG cells are electrically excitable, generating slow periodic voltage spikes and coordinated bursts of Ca2+ oscillations. We revisit data to understand how a multitude of conductances may underlie voltage/Ca2+ oscillations, recognizing that zG layer self-renewal and cell heterogeneity may complicate this task. We review recent data to understand rosette architecture and apply maxims derived from computational network modeling to understand rosette function. The challenge going forward is to uncover how the rosette orchestrates the behavior of a functional network of conditional oscillators to control zG layer performance and aldosterone secretion. Expected final online publication date for the Annual Review of Physiology, Volume 83 is February 10, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Ferrari. Mental disorders in combination with multiple neuritis. (Korsakov's Cerebropathia psychica toxaemica, Polyneuritis Psychosis by other authors). —The Alienist and Neurologist, January 1896, no. 1

Under the name Polyneuritis psychosis, Korsakov described a disease that differs from typical polyneuritis by the predominance of disorders on the part of the mental sphere. It begins with somatic symptoms vomiting, difficulty walking, pain and muscle atrophy; the electrical excitability of the muscles disappears, there are contractures; knee reflex disappears early, others remain normal or even increased. Death occurs from paralysis of the respiratory muscles. As for mental disorders, the last ones appear in the beginning of the disease in the form of simple irritability, after which amnesia comes to the fore.

Correction of disorders of neuronal homeostatic mechanisms in case of neuropsychiatric diseases as a probable direction of drug exposure

The improvement of drug therapy for a number of neuropsychiatric diseases requires the search for new directions of action in comparison with those currently used. Most of the drugs used affect molecular targets that modulate interstructural (interneuronal) interactions. Influencing the deeper processes of synaptic and neuronal homeostasis may be a new direction in the treatment of these diseases. This review examines the mechanisms of homeostatic plasticity of synaptic transmission and electrical excitability of neurons, which balance each other and stabilize the functioning of neurons and neural networks. The first type of homeostatic plasticity is regulated by the intracellular Ca2+ concentration and the activity of protein kinases, and the second one - by membrane density of voltage-dependent ionic channels. Analysis of literature data shows that alterations in some neuro-psychiatric diseases reveal disorders of homeostatic plasticity more often in terms of monodirectional alterations of synaptic impacts and neuronal electrical excitability. Thus, mainly in preclinical studies, it was revealed that stress-induced depressive disorders of behavior are accompanied by a unidirectional increase in pyramidal neurons of 2/3 layers of the prefrontal cortex of rodents, or a weakening in neurons of the 5th layer of synaptic drive and electrical excitability. Similar disorders of homeostatic plasticity were observed by other authors in pyramidal neurons of the dorsolateral prefrontal cortex in schizophrenia, depending on the prevalence of positive or negative symptoms. In chronic neuropathic pain, an increase in the excitability of peripheral neurons of the spinal / trigeminal ganglia, neurons of the dorsal horns, and cortical neurons and an increase in incoming synaptic influences were revealed. The observed disturbances were accompanied by changes in the density of ion channels in neuronal membranes. The peculiarities of the distribution and biophysical properties of voltage-dependent potassium channels allow us to consider them as a probable molecular target for the correction of disorders of homeostatic plasticity.

Feeling the heat: source–sink mismatch as a mechanism underlying the failure of thermal tolerance

ABSTRACTA mechanistic explanation for the tolerance limits of animals at high temperatures is still missing, but one potential target for thermal failure is the electrical signaling off cells and tissues. With this in mind, here I review the effects of high temperature on the electrical excitability of heart, muscle and nerves, and refine a hypothesis regarding high temperature-induced failure of electrical excitation and signal transfer [the temperature-dependent deterioration of electrical excitability (TDEE) hypothesis]. A central tenet of the hypothesis is temperature-dependent mismatch between the depolarizing ion current (i.e. source) of the signaling cell and the repolarizing ion current (i.e. sink) of the receiving cell, which prevents the generation of action potentials (APs) in the latter. A source–sink mismatch can develop in heart, muscles and nerves at high temperatures owing to opposite effects of temperature on source and sink currents. AP propagation is more likely to fail at the sites of structural discontinuities, including electrically coupled cells, synapses and branching points of nerves and muscle, which impose an increased demand of inward current. At these sites, temperature-induced source–sink mismatch can reduce AP frequency, resulting in low-pass filtering or a complete block of signal transmission. In principle, this hypothesis can explain a number of heat-induced effects, including reduced heart rate, reduced synaptic transmission between neurons and reduced impulse transfer from neurons to muscles. The hypothesis is equally valid for ectothermic and endothermic animals, and for both aquatic and terrestrial species. Importantly, the hypothesis is strictly mechanistic and lends itself to experimental falsification.

A novel single-domain Na+-selective voltage-gated channel in photosynthetic eukaryotes

The evolution of Na+-selective four-domain voltage-gated channels (4D-Navs) in animals allowed rapid Na+-dependent electrical excitability, and enabled the development of sophisticated systems for rapid and long-range signalling. Whilst bacteria encode single-domain Na+-selective voltage-gated channels (BacNav), they typically exhibit much slower kinetics than 4D-Navs, and are not thought to have crossed the prokaryote-eukaryote boundary. As such, the capacity for rapid Na+-selective signalling is considered to be confined to certain animal taxa, and absent from photosynthetic eukaryotes. Certainly, in land plants, such as the Venus Flytrap where fast electrical excitability has been described, this is most likely based on fast anion channels. Here, we report a unique class of eukaryotic Na+-selective single-domain channels (EukCatBs) that are present primarily in haptophyte algae, including the ecologically important calcifying coccolithophores. The EukCatB channels exhibit very rapid voltage-dependent activation and inactivation kinetics, and sensitivity to the highly selective 4D-Nav blocker tetrodotoxin. The results demonstrate that the capacity for rapid Na+-based signalling in eukaryotes is not restricted to animals or to the presence of 4D-Navs. The EukCatB channels therefore represent an independent evolution of fast Na+-based electrical signalling in eukaryotes that likely contribute to sophisticated cellular control mechanisms operating on very short time scales in unicellular algae.One Sentence SummaryThe capacity for rapid Na+-based signalling has evolved in ecologically important coccolithophore species via a novel class of voltage-gated Na+ channels, EukCatBs.