L-type of voltage-gated Ca2+ channel

BACKGROUND: The study aimed to identify transcripts of specific ion channels in rat ventricular cardiomyocytes and determine their potential role in the regulation of ionic currents in response to mechanical stimulation. The gene expression levels of various ion channels in freshly isolated rat ventricular cardiomyocytes were investigated using the RNA-seq technique. We also measured changes in current through CaV 1.2 channels under cell stretching using the whole-cell patch-clamp method...

α2-Adrenoreceptors (ARs) are main Gi -protein coupled autoreceptors in sympathetic nerve terminals and targets for dexmedetomidine (DEX), a widely used sedative. We hypothesize that α2-ARs are also potent regulators of neuromuscular transmission via G protein-gated inwardly rectifying potassium (GIRK) channels. Using extracellular microelectrode recording of postsynaptic potentials, we found DEX-induced inhibition of spontaneous and evoked neurotransmitter release as well as desynchronization of evoked exocytotic events in the mouse diaphragm neuromuscular junction...

Dihydropyridines such as amlodipine are widely used as antihypertensive agents, being prescribed to ∼70 million Americans and >0.4 billion adults worldwide. Dihydropyridines block voltage-gated Ca2+ channels in resistance vessels, leading to vasodilation and a reduction in blood pressure. Various meta-analyses show that dihydropyridines are relatively safe and effective in reducing hypertension. The use of dihydropyridines has recently been called into question as these drugs appear to activate store-operated Ca2+ entry in fura-2-loaded nonexcitable cells, trigger vascular remodeling, and increase heart failure, leading to the questioning of their clinical use...

Excitation-transcription coupling (E-TC) links synaptic and cellular activity to nuclear gene transcription. It is generally accepted that E-TC makes a crucial contribution to learning and memory through its role in underpinning long-lasting synaptic enhancement in late-phase long-term potentiation and has more recently been linked to late-phase long-term depression: both processes require de novo gene transcription, mRNA translation and protein synthesis. E-TC begins with the activation of glutamate-gated N-methyl-D-aspartate-type receptors and voltage-gated L-type Ca2+ channels at the membrane and culminates in the activation of transcription factors in the nucleus...

Many neurons exhibit regular firing that is limited to the duration and intensity of depolarizing stimuli. However, some neurons exhibit all-or-nothing plateau potentials that, once elicited, can lead to prolonged activity that is independent of stimulus intensity or duration. To better understand this diversity of information processing, we compared the voltage- and Ca2+ -gated currents of three identified neurons from hermaphroditic Aplysia californica Two of these neurons, B51 and B64, generated plateau potentials and a third neuron, B8, exhibited regular firing and was incapable of generating a plateau potential...

Progressive damage of retinal ganglion cells (RGCs) is observed in early diabetic retinopathy. Intracellular Ca2+ overload mediated by Ca2+ influx through voltage-gated Ca2+ channels (VGCCs) is involved in neurodegeneration, whereas glucagon-like peptide-1 (GLP-1) provides neuroprotection. However, whether GLP-1 plays a neuroprotective role in diabetic retinas by modulating VGCCs remains unknown. We found that eye drops of exendin-4, a long-acting GLP-1 receptor (GLP-1R) agonist, prevented the increase of L-type Ca2+ current ( I LCa ) densities of RGCs induced by 4-week hyperglycemia and promoted RGC survival by suppressing L-type VGCC (L-VGCC) activity in streptozotocin-induced diabetic rats...

Voltage-gated Ca2+ channels (VGCC) directly control muscle contraction and neurotransmitter release, and slower processes such as cell differentiation, migration, and death. They are potently inhibited by RGK GTP-ases (Rem, Rem2, Rad, and Gem/Kir), which decrease Ca2+ channel membrane expression, as well as directly inhibit membrane-resident channels. The mechanisms of membrane-resident channel inhibition are difficult to study because RGK-overexpression causes complete or near complete channel inhibition. Using titrated levels of Gem expression in Xenopus oocytes to inhibit WT P/Q-type calcium channels by ∼50%, we show that inhibition is dependent on channel inactivation...

BACKGROUND: Transcranial ultrasound stimulation (TUS) is a novel non-invasive brain stimulation technique with high depth penetrance and spatial resolution. Theta-burst TUS (tbTUS) is a plasticity-inducing protocol which increases motor cortical excitability for up to 30 min following 80s of sonication. While this protocol may have therapeutic potential for the treatment of psychiatric and neurological disorders, the mechanisms of action of TUS remain unclear. OBJECTIVE: We conducted the first pharmacological study to examine the mechanisms of TUS in human primary motor cortex...

Nuclear Ca2+ waves elicited by NMDAR and L-type voltage-gated Ca2+ -channels as well as protein transport from synapse-to-nucleus are both instrumental in control of plasticity-related gene expression. At present it is not known whether fast [Ca2+ ]n transients converge in the nucleus with signaling of synapto-nuclear protein messenger. Jacob is a protein that translocate a signalosome from N-methyl-D-aspartate receptors (NMDAR) to the nucleus and that docks this signalosome to the transcription factor CREB...

Skeletal muscle fibers express distinct gene programs during development and maturation, but the underlying gene regulatory networks that confer stage-specific myofiber properties remain unknown. To decipher these distinctive gene programs and how they respond to neural activity, we generated a combined multi-omic single-nucleus RNA-seq and ATAC-seq atlas of mouse skeletal muscle development at multiple stages of embryonic, fetal, and postnatal life. We found that Myogenin, Klf5, and Tead4 form a transcriptional complex that synergistically activates the expression of muscle genes in developing myofibers...

BACKGROUND AND PURPOSE: Raised serum concentrations of the sympathetic co-transmitter neuropeptide Y (NPY) are linked to cardiovascular diseases. However, the signalling mechanism for vascular smooth muscle (VSM) constriction to NPY is poorly understood. Therefore, the present study investigated the mechanisms of NPY-induced vasoconstriction in rat small mesenteric (RMA) and coronary (RCA) arteries. EXPERIMENTAL APPROACH: Third order mesenteric or intra-septal arteries from male Wistar rats were assessed in wire myographs for isometric tension, VSM membrane potential, VSM intracellular Ca2+ events...

Cardiac excitation-contraction coupling (ECC) depends on Ca2+ release from intracellular stores via ryanodine receptors (RyRs) triggered by L-type Ca2+ channels (LCCs). Uncertain numbers of RyRs and LCCs form 'couplons' whose activation produces Ca2+ sparks, which summate to form a cell-wide Ca2+ transient that switches on contraction. Voltage (Vm ) changes during the action potential (AP) and stochasticity in channel gating should create variability in Ca2+ spark timing, but Ca2+ transient wavefronts have remarkable uniformity...

Englerin A (EA) is a potent agonist of tetrameric transient receptor potential canonical (TRPC) ion channels containing TRPC4 and TRPC5 subunits. TRPC proteins form cation channels that are activated by plasma membrane receptors. They convert extracellular signals such as angiotensin II into cellular responses, whereupon Na+ and Ca2+ influx and depolarization of the plasma membrane occur. Via depolarization, voltage-gated Ca2+ (CaV) channels can be activated, further increasing Ca2+ influx. We investigated the extent to which EA also affects the functions of CaV channels using the high-voltage-activated L-type Ca2+ channel CaV1...

Burst activity is a ubiquitous feature of thalamic neurons and is well documented for visual neurons in the lateral geniculate nucleus (LGN). Although bursts are often associated with states of drowsiness, they are also known to convey visual information to cortex and are particularly effective in evoking cortical responses. The occurrence of thalamic bursts depends on (1) the inactivation gate of T-type Ca2+ channels (T-channels), which become de-inactivated following periods of increased membrane hyperpolarization, and (2) the opening of the T-channel activation gate, which has voltage-threshold and rate-of-change (δv/δt) requirements...

Clustering of L-type voltage-gated Ca2+ channels (LTCCs) in the plasma membrane is increasingly implicated in creating highly localized Ca2+ signaling nanodomains. For example, neuronal LTCC activation can increase phosphorylation of the nuclear CREB transcription factor by increasing Ca2+ concentrations within a nanodomain close to the channel, without requiring bulk Ca2+ increases in the cytosol or nucleus. However, the molecular basis for LTCC clustering is poorly understood. The postsynaptic scaffolding protein Shank3 specifically associates with one of the major neuronal LTCCs, the CaV 1...

Benzodiazepines are among the most prescribed drug class worldwide to treat disorders such as anxiety, insomnia, muscle spasticity, and convulsive disorders, and to induce presurgical sedation. Although benzodiazepines exhibit a high therapeutic index and low toxicity in short-term treatments, prolonged administration induces tolerance to most of their therapeutic actions. The mechanism of this tolerance remains unclear. The central actions of benzodiazepines are mediated by binding to GABAA receptors, which mediate most fast inhibitory transmission in the brain...

Tendons are tension-bearing tissues transmitting force from muscle to bone for body movement. This mechanical loading is essential for tendon development, homeostasis, and healing after injury. While Ca2+ signaling has been studied extensively for its roles in mechanotransduction, regulating muscle, bone, and cartilage development and homeostasis, knowledge about Ca2+ signaling and the source of Ca2+ signals in tendon fibroblast biology are largely unknown. Here, we investigated the function of Ca2+ signaling through CaV 1...

Omecamtiv mecarbil (OM, CK-1827452) is recognized as an activator of myosin and has been demonstrated to be beneficial for the treatment of systolic heart failure. However, the mechanisms by which this compound interacts with ionic currents in electrically excitable cells remain largely unknown. The objective of this study was to investigate the effects of OM on ionic currents in GH3 pituitary cells and Neuro-2a neuroblastoma cells. In GH3 cells, whole-cell current recordings showed that the addition of OM had different potencies in stimulating the transient ( I Na(T) ) and late components ( I Na(L) ) of the voltage-gated Na+ current ( I Na ) with different potencies in GH3 cells...

TRP channels are expressed both in vascular myocytes and endothelial cells, but knowledge of their operational mechanisms in vascular tissue is particularly limited. Here, we show for the first time the biphasic contractile reaction with relaxation followed by a contraction in response to TRPV4 agonist, GSK1016790A, in a rat pulmonary artery preconstricted with phenylephrine. Similar responses were observed both with and without endothelium, and these were abolished by the TRPV4 selective blocker, HC067047, confirming the specific role of TRPV4 in vascular myocytes...

ETHNOPHARMACOLOGICAL RELEVANCE: Prangos ferulacea (L.) Lindl is an Apiaceae plant, widely used in traditional medicine. Recently, chemical composition and biological activities of its essential oil (Prangroil) have been reported, but there are no studies on possible effects on intestinal contractility. AIMS OF THE STUDY: We investigated the effects of essential oil Sicilian Prangoil on the contractility of rat small (duodenum) and large (colon) intestine and the related action mechanism...