Cardiovascular function depends on an adequate vascular tone facilitating appropriate blood flow to individual tissues according to their needs. The tone results from the interplay between vasodilatation and vasoconstriction. Its rapid and efficient regulation is secured by many interconnected physiological mechanisms, both at the level of the vascular smooth muscle and the endothelium. The purpose of this review is to provide an update of the current knowledge on the mechanisms of physiological vasodilatation. First, two principal intracellular signaling pathways linked to the activation of protein kinases PKA and PKG are introduced. Subsequently, the role of endothelium-derived relaxing factors together with the endothelium-dependent hyperpolarization is discussed. The roles of ion channels and gap junctions in the communication between endothelium and vascular smooth muscle cells are particularly discussed. Finally, principal vasodilatory stimuli (mechanical, thermal, chemical) and their mechanisms of action are briefly introduced.

• Keywords
• EDRF, NO, PKA, PKG, Vasodilatation,
• MeSH
• Endothelium, Vascular physiology   MeSH
• Ion Channels physiology   MeSH
• Humans MeSH
• Gap Junctions physiology   MeSH
• Cyclic AMP-Dependent Protein Kinases metabolism   MeSH
• Cyclic GMP-Dependent Protein Kinases metabolism   MeSH
• Signal Transduction physiology   MeSH
• Muscle, Smooth, Vascular physiology   MeSH
• Vasodilation * physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Ion Channels MeSH
• Cyclic AMP-Dependent Protein Kinases MeSH
• Cyclic GMP-Dependent Protein Kinases MeSH

The ERG6 gene is crucial for the biosynthesis of ergosterol, a key component of yeast cell membranes. Our study examines the impact of ERG6 gene deletion on the membrane composition and physicochemical properties of the pathogenic yeast Candida glabrata. Specifically, we investigated changes in selected sterol content, phospholipid composition, transmembrane potential, and PDR16 gene activity. Sterol levels were measured using high-performance liquid chromatography, the phospholipid profile was analysed via thin-layer chromatography, transmembrane potential was assessed with fluorescence spectroscopy, and gene expression levels were determined by quantitative PCR. Our findings revealed a depletion of ergosterol, increased zymosterol and eburicol content, an increased phosphatidylcholine and a reduced phosphatidylethanolamine content in the Δerg6 strain compared to the wt. Additionally, the Δerg6 strain exhibited membrane hyperpolarization without changes in PDR16 expression. Furthermore, the Δerg6 strain showed increased sensitivity to the antifungals myriocin and aureobasidine A. These results suggest that ERG6 gene deletion leads to significant alterations in membrane composition and may activates an alternative ergosterol synthesis pathway in the C. glabrata Δerg6 deletion mutant.

• Keywords
• Candida glabrata, ERG6, Eburicol, Ergosterol, Phospholipids, Transmembrane potential,
• MeSH
• Antifungal Agents pharmacology   MeSH
• Cell Membrane * metabolism   chemistry   drug effects   MeSH
• Candida glabrata * genetics   metabolism   drug effects   cytology   MeSH
• Gene Deletion * MeSH
• Ergosterol metabolism   biosynthesis   MeSH
• Phospholipids metabolism   MeSH
• Fungal Proteins * genetics   metabolism   MeSH
• Membrane Potentials drug effects   MeSH
• Gene Expression Regulation, Fungal MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antifungal Agents MeSH
• Ergosterol MeSH
• Phospholipids MeSH
• Fungal Proteins * MeSH

Mutations in CACNA1C, the gene encoding Cav1.2 voltage-gated calcium channels, are associated with a spectrum of disorders, including Timothy syndrome and other neurodevelopmental and cardiac conditions. In this study, we report a child with a de novo heterozygous missense variant (c.1973T > C; L658P) in CACNA1C, presenting with refractory epilepsy, global developmental delay, hypotonia, and multiple systemic abnormalities, but without overt cardiac dysfunction. Electrophysiological analysis of the recombinant Cav1.2 L658P variant revealed profound gating alterations, most notably a significant hyperpolarizing shift in the voltage dependence of activation and inactivation. Additionally, molecular modeling suggested that the L658P mutation disrupts interactions within the IIS5 transmembrane segment, reducing the energy barrier for state transitions and facilitating channel opening at more negative voltages. These findings establish L658P as a pathogenic CACNA1C variant primarily associated with severe neurological dysfunction and expands the phenotypic spectrum of CACNA1C-related disorders.

• Keywords
• CACNA1C, Calcium channel, Cav1.2, Channelopathies, Electrophysiology, L658P,
• MeSH
• Child MeSH
• Ion Channel Gating MeSH
• HEK293 Cells MeSH
• Humans MeSH
• Mutation, Missense genetics   MeSH
• Models, Molecular MeSH
• Mutation * genetics   MeSH
• Neurodevelopmental Disorders * genetics   physiopathology   MeSH
• Amino Acid Sequence MeSH
• Calcium Channels, L-Type * genetics   chemistry   metabolism   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Names of Substances
• CACNA1C protein, human MeSH Browser
• Calcium Channels, L-Type * MeSH

During GABAergic synaptic transmission, G protein-coupled GABAB receptors (GBRs) activate K+ channels that prolong the duration of inhibitory postsynaptic potentials (IPSPs). We now show that KCTD16, an auxiliary GBR subunit, anchors hyperpolarization-activated cyclic nucleotide-gated (HCN) channels containing HCN2/HCN3 subunits to GBRs. In dopamine neurons of the VTA (DAVTA neurons), this interaction facilitates activation of HCN channels via hyperpolarization during IPSPs, counteracting the GBR-mediated late phase of these IPSPs. Consequently, disruption of the GBR/HCN complex in KCTD16-/- mice leads to prolonged optogenetic inhibition of DAVTA neuron firing. KCTD16-/- mice exhibit increased anxiety-like behavior in response to stress - a behavior replicated by CRISPR/Cas9-mediated KCTD16 ablation in DAVTA neurons or by intra-VTA infusion of an HCN antagonist in wild-type mice. Our findings support that the retention of HCN channels at GABAergic synapses by GBRs in DAVTA neurons provides a negative feedback mechanism that restricts IPSP duration and mitigates the development of anxiety.

• Keywords
• GABA-A, GABA-B, HCN2, Hyperpolarization-activated cyclic nucleotide-gated channels, Late IPSP, Optogenetic inhibition, Slow IPSP,
• MeSH
• Dopaminergic Neurons * metabolism   MeSH
• Potassium Channels metabolism   MeSH
• Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels * metabolism   MeSH
• Inhibitory Postsynaptic Potentials physiology   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Neural Inhibition * physiology   MeSH
• Receptors, GABA-B * metabolism   MeSH
• Ventral Tegmental Area * metabolism   MeSH
• Anxiety * metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Potassium Channels MeSH
• Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels * MeSH
• Receptors, GABA-B * MeSH

The somatostatin (SST) receptor family controls pituitary hormone secretion, but the distribution and specific roles of these receptors on the excitability and voltage-gated calcium signaling of hormone producing pituitary cells have not been fully characterized. Here we show that the rat pituitary gland expressed Sstr1, Sstr2, Sstr3, and Sstr5 receptor genes in a cell type-specific manner: Sstr1 and Sstr2 in thyrotrophs, Sstr3 in gonadotrophs and lactotrophs, Sstr2, Sstr3, and Sstr5 in somatotrophs, and none in corticotrophs and melanotrophs. Most gonadotrophs and thyrotrophs spontaneously fired high-amplitude single action potentials, which were silenced by SST without affecting intracellular calcium concentrations. In contrast, lactotrophs and somatotrophs spontaneously fired low-amplitude plateau-bursting action potentials in conjunction with calcium transients, both of which were silenced by SST. Moreover, SST inhibited GPCR-induced voltage-gated calcium signaling and hormone secretion in all cell types expressing SST receptors, but the inhibition was more pronounced in somatotrophs. The pattern of inhibition of electrical activity and calcium signaling was consistent with both direct and indirect inhibition of voltage-gated calcium channels, the latter being driven by cell type-specific hyperpolarization. These results indicate that the action of SST in somatotrophs is enhanced by the expression of several types of SST receptors and their slow desensitization, that SST may play a role in the electrical resynchronization of gonadotrophs, thyrotrophs, and lactotrophs, and that the lack of SST receptors in corticotrophs and melanotrophs keeps them excitable and ready to responses to stress.

• Keywords
• Gonadotrophs, Lactotrophs, Pituitary, Somatostatin receptors, Somatotrophs, Thyrotrophs, Voltage-gated calcium influx,
• MeSH
• Action Potentials drug effects   MeSH
• Gonadotrophs metabolism   drug effects   MeSH
• Pituitary Gland * metabolism   MeSH
• Rats MeSH
• Rats, Wistar MeSH
• Receptors, Somatostatin * metabolism   genetics   MeSH
• Somatostatin metabolism   MeSH
• Calcium metabolism   MeSH
• Calcium Signaling * drug effects   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Receptors, Somatostatin * MeSH
• somatostatin receptor 5 MeSH Browser
• Somatostatin MeSH
• Calcium MeSH

Viral infection may represent a stress condition to the host cell. Cells react to it by triggering the defence programme to restore homeostasis and these events may in turn impact the viral replication. The knowledge about tick-borne encephalitis virus (TBEV) infection-associated stress is limited. Here we investigated the interplay between TBEV infection and stress pathways in PMJ2-R mouse macrophage cell line, as macrophages are the target cells in early phases of TBEV infection. First, to determine how stress influences TBEV replication, the effect of stress inducers H2O2 and tunicamycin (TM) was tested. Viral multiplication was decreased in the presence of both stress inducers suggesting that the stress and cellular stress responses restrict the virus replication. Second, we investigated the induction of oxidative stress and endoplasmic reticulum (ER) stress upon TBEV infection. The level of oxidative stress was interrogated by measuring the reactive oxygen species (ROS). ROS were intermittently increased in infected cells at 12 hpi and at 72 hpi. As mitochondrial dysfunction may result in increased ROS level, we evaluated the mitochondrial homeostasis by measuring the mitochondrial membrane potential (MMP) and found that TBEV infection induced the hyperpolarization of MMP. Moreover, a transient increase of gene expression of stress-induced antioxidative enzymes, like p62, Gclm and Hmox1, was detected. Next, we evaluated the ER stress upon TBEV infection by analysing unfolded protein responses (UPR). We found that infection induced gene expression of two general sensors BiP and CHOP and activated the IRE1 pathway of UPR. Finally, since the natural transmission route of TBEV from its tick vector to the host is mediated via tick saliva, the impact of tick saliva from Ixodes ricinus on stress pathways in TBEV-infected cells was tested. We observed only marginal potentiation of UPR pathway. In conclusion, we found that TBEV infection of PMJ2-R cells elicits the changes in redox balance and triggers cellular stress defences, including antioxidant responses and the IRE1 pathway of UPR. Importantly, our results revealed the negative effect of stress-evoked events on TBEV replication and only marginal impact of tick saliva on stress cellular pathways.

• Keywords
• Cellular stress, Flavivirus, Mitochondrial homeostasis, Oxidative stress, Stress on endoplasmic reticulum, Tick saliva, Tick-borne encephalitis virus, Unfolded protein response, Virus replication,
• MeSH
• Cell Line MeSH
• Encephalitis, Tick-Borne * MeSH
• Mice MeSH
• Hydrogen Peroxide metabolism   MeSH
• Protein Serine-Threonine Kinases metabolism   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Virus Replication MeSH
• Encephalitis Viruses, Tick-Borne * genetics   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Hydrogen Peroxide MeSH
• Protein Serine-Threonine Kinases MeSH
• Reactive Oxygen Species MeSH

Somatosensory information is propagated from the periphery to the cerebral cortex by two parallel pathways through the ventral posterolateral (VPL) and ventral posteromedial (VPM) thalamus. VPL and VPM neurons receive somatosensory signals from the body and head, respectively. VPL and VPM neurons may also receive cell type-specific GABAergic input from the reticular nucleus of the thalamus. Although VPL and VPM neurons have distinct connectivity and physiological roles, differences in their functional properties remain unclear as they are often studied as one ventrobasal thalamus neuron population. Here, we directly compared synaptic and intrinsic properties of VPL and VPM neurons in C57Bl/6J mice of both sexes aged P25-P32. VPL neurons showed greater depolarization-induced spike firing and spike frequency adaptation than VPM neurons. VPL and VPM neurons fired similar numbers of spikes during hyperpolarization rebound bursts, but VPM neurons exhibited shorter burst latency compared with VPL neurons, which correlated with larger sag potential. VPM neurons had larger membrane capacitance and more complex dendritic arbors. Recordings of spontaneous and evoked synaptic transmission suggested that VPL neurons receive stronger excitatory synaptic input, whereas inhibitory synapse strength was stronger in VPM neurons. This work indicates that VPL and VPM thalamocortical neurons have distinct intrinsic and synaptic properties. The observed functional differences could have important implications for their specific physiological and pathophysiological roles within the somatosensory thalamocortical network.NEW & NOTEWORTHY This study revealed that somatosensory thalamocortical neurons in the VPL and VPM have substantial differences in excitatory synaptic input and intrinsic firing properties. The distinct properties suggest that VPL and VPM neurons could process somatosensory information differently and have selective vulnerability to disease. This work improves our understanding of nucleus-specific neuron function in the thalamus and demonstrates the critical importance of studying these parallel somatosensory pathways separately.

• Keywords
• somatosensory thalamus, synaptic transmission, thalamocortical neuron, ventral posterolateral nucleus, ventral posteromedial nucleus,
• MeSH
• Cerebral Cortex MeSH
• Mice MeSH
• Synaptic Transmission physiology   MeSH
• Neurons * physiology   MeSH
• Somatosensory Cortex physiology   MeSH
• Synapses physiology   MeSH
• Thalamus * physiology   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Pheochromocytomas/paragangliomas (PPGLs) are neuroendocrine tumours, mostly resulting from mutations in predisposing genes. Mutations of succinate dehydrogenase (SDH) subunit B (SDHB) are associated with high probability of metastatic disease. Since bioelectrical properties and signalling in cancer are an emerging field, we investigated the metabolic, functional and electrophysiological characteristics in human succinate dehydrogenase subunit B (SDHB)-deficient pheochromocytoma cells. These cells exhibited reduced SDH function with elevated succinate-to-fumarate ratio and reduced intracellular ATP levels. The analysis of membrane passive properties revealed a more hyperpolarized membrane potential and a lower cell capacitance of SDHB-deficient cells compared to the parental ones. These bioelectrical changes were associated with reduced proliferation and adhesion capacity of SDHB-deficient cells. Only in SDHB-deficient cells, we also observed an increased amplitude of potassium currents suggesting an activation of ATP-sensitive potassium channels (KATP). Indeed, exposure of the SDHB-deficient cells to glibenclamide, a specific KATP inhibitor, or to ATP caused normalization of potassium current features and altered proliferation and adhesion. In this work, we show for the first time that reduced intracellular ATP levels in SDHB-deficient chromaffin cells impaired cell bioelectrical properties, which, in turn, are associated with an increased cell aggressiveness. Moreover, we first ever demonstrated that glibenclamide not only reduced the outward potassium currents in SDHB-deficient cells but increased their growth capacity, reduced their ability to migrate and shifted their phenotype towards one more similar to that of parental one.

• Keywords
• ATP-sensitive potassium channels, bioelectrical properties, glibenclamide, pheochromocytoma/paraganglioma, succinate dehydrogenase,
• MeSH
• Adenosine Triphosphate MeSH
• Chromaffin Cells * metabolism   pathology   MeSH
• Pheochromocytoma * genetics   MeSH
• Glyburide pharmacology   MeSH
• Humans MeSH
• Adrenal Gland Neoplasms * genetics   MeSH
• Paraganglioma * genetics   MeSH
• Succinate Dehydrogenase genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adenosine Triphosphate MeSH
• Glyburide MeSH
• Succinate Dehydrogenase MeSH

Fluorinated Metal-Organic Frameworks (MOFs), comprising a wheel-shaped ligand with geminal rotating fluorine atoms, produced benchmark mobility of correlated dipolar rotors at 2 K, with practically null activation energy (Ea =17 cal mol-1 ). 1 H T1 NMR revealed multiple relaxation phenomena due to the exchange among correlated dipole-rotor configurations. Synchrotron radiation X-ray diffraction at 4 K, Density Functional Theory, Molecular Dynamics and phonon calculations showed the fluid landscape and pointed out a cascade mechanism converting dipole configurations into each other. Gas accessibility, shown by hyperpolarized-Xe NMR, allowed for chemical stimuli intervention: CO2 triggered dipole reorientation, reducing their collective dynamics and stimulating a dipole configuration change in the crystal. Dynamic materials under limited thermal noise and high responsiveness enable the fabrication of molecular machines with low energy dissipation and controllable dynamics.

• Keywords
• Crystal Engineering, Fluorine, Metal Organic Frameworks, Molecular Dynamics, Molecular Rotor,
• Publication type
• Journal Article MeSH

Stress responses are activated by the hypothalamic-pituitary-adrenal axis (HPA axis), culminating in the release of glucocorticoids. During prolonged periods of secretion of glucocorticoids or inappropriate behavioral responses to a stressor, pathologic conditions may occur. Increased glucocorticoid concentration is linked to generalized anxiety, and there are knowledge gaps regarding its regulation. It is known that the HPA axis is under GABAergic control, but the contribution of the individual subunits of the GABA receptor is largely unknown. In this study, we investigated the relationship between the α5 subunit and corticosterone levels in a new mouse model deficient for Gabra5, which is known to be linked to anxiety disorders in humans and phenologs observed in mice. We observed decreased rearing behavior, suggesting lower anxiety in the Gabra5-/- animals; however, such a phenotype was absent in the open field and elevated plus maze tests. In addition to decreased rearing behavior, we also found decreased levels of fecal corticosterone metabolites in Gabra5-/- mice indicating a lowered stress response. Moreover, based on the electrophysiological recordings where we observed a hyperpolarized state of hippocampal neurons, we hypothesize that the constitutive ablation of the Gabra5 gene leads to functional compensation with other channels or GABA receptor subunits in this model.

• Keywords
• GABA receptor, anxiety, behavior, corticosterone, mouse model,
• MeSH
• Glucocorticoids * MeSH
• Corticosterone * MeSH
• Humans MeSH
• Mice MeSH
• Receptors, GABA-A genetics   metabolism   MeSH
• Receptors, GABA metabolism   MeSH
• Pituitary-Adrenal System metabolism   MeSH
• Hypothalamo-Hypophyseal System metabolism   MeSH
• Anxiety MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• GABRA5 protein, human MeSH Browser
• Gabra5 protein, mouse MeSH Browser
• Glucocorticoids * MeSH
• Corticosterone * MeSH
• Receptors, GABA-A MeSH
• Receptors, GABA MeSH