Isoprenylated Flavonoids as Cav3.1 Low Voltage-Gated Ca2+ Channel Inhibitors from Salvia digitaloides.
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ABSTRACT:
SUBMITTER: Zhao JJ
PROVIDER: S-EPMC8599534 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:All cells, including nonexcitable cells, maintain a discrete transmembrane potential (V mem), and have the capacity to modulate V mem and respond to their own and neighbors' changes in V mem Spatiotemporal variations have been described in developing embryonic tissues and in some cases have been implicated in influencing developmental processes. Yet, how such changes in V mem are converted into intracellular inputs that in turn regulate developmental gene expression and coordinate patterned tissue formation, has remained elusive. Here we document that the V mem of limb mesenchyme switches from a hyperpolarized to depolarized state during early chondrocyte differentiation. This change in V mem increases intracellular Ca2+ signaling through Ca2+ influx, via CaV1.2, 1 of L-type voltage-gated Ca2+ channels (VGCCs). We find that CaV1.2 activity is essential for chondrogenesis in the developing limbs. Pharmacological inhibition by an L-type VGCC specific blocker, or limb-specific deletion of CaV1.2, down-regulates expression of genes essential for chondrocyte differentiation, including Sox9, Col2a1, and Agc1, and thus disturbs proper cartilage formation. The Ca2+-dependent transcription factor NFATc1, which is a known major transducer of intracellular Ca2+ signaling, partly rescues Sox9 expression. These data reveal instructive roles of CaV1.2 in limb development, and more generally expand our understanding of how modulation of membrane potential is used as a mechanism of developmental regulation.
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Project description:Diltiazem is a widely prescribed Ca2+ antagonist drug for cardiac arrhythmia, hypertension, and angina pectoris. Using the ancestral CaV channel construct CaVAb as a molecular model for X-ray crystallographic analysis, we show here that diltiazem targets the central cavity of the voltage-gated Ca2+ channel underneath its selectivity filter and physically blocks ion conduction. The diltiazem-binding site overlaps with the receptor site for phenylalkylamine Ca2+ antagonist drugs such as verapamil. The dihydropyridine Ca2+ channel blocker amlodipine binds at a distinct site and allosterically modulates the binding sites for diltiazem and Ca2+ Our studies resolve two distinct binding poses for diltiazem in the absence and presence of amlodipine. The binding pose in the presence of amlodipine may mimic a high-affinity binding configuration induced by voltage-dependent inactivation, which is favored by dihydropyridine binding. In this binding pose, the tertiary amino group of diltiazem projects upward into the inner end of the ion selectivity filter, interacts with ion coordination Site 3 formed by the backbone carbonyls of T175, and alters binding of Ca2+ to ion coordination Sites 1 and 2. Altogether, our results define the receptor site for diltiazem and elucidate the mechanisms for pore block and allosteric modulation by other Ca2+ channel-blocking drugs at the atomic level. SIGNIFICANCE STATEMENT: Calcium antagonist drugs that block voltage-gated calcium channels in heart and vascular smooth muscle are widely used in the treatment of cardiovascular diseases. Our results reveal the chemical details of diltiazem binding in a blocking position in the pore of a model calcium channel and show that binding of another calcium antagonist drug alters binding of diltiazem and calcium. This structural information defines the mechanism of drug action at the atomic level and provides a molecular template for future drug discovery.
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Project description:Voltage-gated Ca2+ channels are typically integrated in a complex network of protein-protein-interactions, also referred to as Ca2+ channel nanodomains. Amongst the neuronal CaV2 channel family, CaV2.2 is of particular importance due to its general role for signal transmission from the periphery to the central nervous system, but also due to its significance for pain perception. Thus, CaV2.2 is an ideal target candidate to search for pharmacological inhibitors but also for novel modulatory interactors. In this review we summarize the last years findings of our intense screenings and characterization of the six CaV2.2 interaction partners, tetraspanin-13 (TSPAN-13), reticulon 1 (RTN1), member 1 of solute carrier family 38 (SLC38), prostaglandin D2 synthase (PTGDS), transmembrane protein 223 (TMEM223), and transmembrane BAX inhibitor motif 3 (Grina/TMBIM3) containing protein. Each protein shows a unique way of channel modulation as shown by extensive electrophysiological studies. Amongst the newly identified interactors, Grina/TMBIM3 is most striking due to its modulatory effect which is rather comparable to G-protein regulation.
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Project description:Disrupted in Schizophrenia 1 (DISC1) participates in a wide variety of developmental processes of central neurons. It also serves critical roles that underlie cognitive functioning in adult central neurons. Here we summarize DISC1's general properties and discuss its use as a model system for understanding major mental illnesses (MMIs). We then discuss the cellular actions of DISC1 that involve or regulate Ca2+ signaling in adult central neurons. In particular, we focus on the tethering role DISC1 plays in transporting RNA particles containing Ca2+ channel subunit RNAs, including IP3R1, CACNA1C and CACNA2D1, and in transporting mitochondria into dendritic and axonal processes. We also review DISC1's role in modulating IP3R1 activity within mitochondria-associated ER membrane (MAM). Finally, we discuss DISC1-glycogen synthase kinase 3β (GSK3β) signaling that regulates functional expression of voltage-gated Ca2+ channels (VGCCs) at central synapses. In each case, DISC1 regulates the movement of molecules that impact Ca2+ signaling in neurons.
| S-EPMC8663806 | biostudies-literature
Project description:This article provides raw relative electroencephalographic (EEG) power, temperature and activity data from controls and Cav3.2 deficient mice. Radiotransmitter implantation was carried out in male experimental mice under ketamine/xylazine narcosis. Following a recovery period, radiotelemetric EEG recordings from the hippocampal CA1 region were obtained under spontaneous 24 h long-term conditions and post urethane injection. Relative EEG power values (%) for 2 s epochs were analysed for the following frequency ranges: delta 1 ( δ1 , 0.5-4 Hz), delta 2 ( δ2 , 1-4 Hz), theta 1 ( θ1 , 4-8 Hz), theta 2 ( θ2 , 4-12 Hz), alpha ( α , 8-12 Hz), sigma ( σ , 12-16 Hz), beta 1 ( β1 , 12-30 Hz), beta 2 ( β2 , 16-24 Hz), beta 3 ( β3 , 16-30 Hz), gamma low ( γlow , 30-50 Hz), gamma mid ( γmid , 50-70 Hz), gamma high ( γhigh , 70-100 Hz), gamma ripples ( γripples , 80-200 Hz), and gamma fast ripples ( γfastripples , 200-500 Hz). In addition, subcutaneous temperature and relative activity data were analysed for both the light and dark cycle of two long-term recordings. The same type of data was obtained post urethane injection. Detailed information is provided for the age and body weight of the experimental animals, the technical specifications of the radiofrequency transmitter, the stereotaxic coordinates for the intracerebral, deep and epidural, surface EEG electrodes, the electrode features, the filtering and sampling characteristics, the analysed EEG frequency bands and the data acquisition parameters. EEG power data, temperature and activity data are available at MENDELEY DATA (doi:10.17632/x53km5sby6.1, URL: http://dx.doi.org/10.17632/x53km5sby6.1). Raw EEG data are available at zenodo (https://zenodo.org/).
| S-EPMC8080467 | biostudies-literature
Project description:Voltage-gated Ca2+ channels are key transducers of cellular excitability and participate in several crucial physiological responses. In vertebrates, 10 Ca2+ channel genes, grouped in 3 families (CaV1, CaV2 and CaV3), have been described and characterized. Insects possess only one member of each family. These genes have been isolated in a limited number of species and very few have been characterized although, in addition to their crucial role, they may represent a collateral target for neurotoxic insecticides. We have isolated the 3 genes coding for the 3 Ca2+ channels expressed in Apis mellifera. This work provides the first detailed characterization of the honeybee T-type CaV3 Ca2+ channel and demonstrates the low toxicity of inhibiting this channel. Comparing Ca2+ currents recorded in bee neurons and myocytes with Ca2+ currents recorded in Xenopus oocytes expressing the honeybee CaV3 gene suggests native expression in bee muscle cells only. High-voltage activated Ca2+ channels could be recorded in the somata of different cultured bee neurons. These functional data were confirmed by in situ hybridization, immunolocalization and in vivo analysis of the effects of a CaV3 inhibitor. The biophysical and pharmacological characterization and the tissue distribution of CaV3 suggest a role in honeybee muscle function.
| S-EPMC5286435 | biostudies-literature
Project description:Voltage-gated Cav1.2 and Cav1.3 (L-type) Ca2+ channels regulate neuronal excitability, synaptic plasticity, and learning and memory. Densin-180 (densin) is an excitatory synaptic protein that promotes Ca2+-dependent facilitation of voltage-gated Cav1.3 Ca2+ channels in transfected cells. Mice lacking densin (densin KO) exhibit defects in synaptic plasticity, spatial memory, and increased anxiety-related behaviors-phenotypes that more closely match those in mice lacking Cav1.2 than Cav1.3. Therefore, we investigated the functional impact of densin on Cav1.2. We report that densin is an essential regulator of Cav1.2 in neurons, but has distinct modulatory effects compared with its regulation of Cav1.3. Densin binds to the N-terminal domain of Cav1.2, but not that of Cav1.3, and increases Cav1.2 currents in transfected cells and in neurons. In transfected cells, densin accelerates the forward trafficking of Cav1.2 channels without affecting their endocytosis. Consistent with a role for densin in increasing the number of postsynaptic Cav1.2 channels, overexpression of densin increases the clustering of Cav1.2 in dendrites of hippocampal neurons in culture. Compared with wild-type mice, the cell surface levels of Cav1.2 in the brain, as well as Cav1.2 current density and signaling to the nucleus, are reduced in neurons from densin KO mice. We conclude that densin is an essential regulator of neuronal Cav1 channels and ensures efficient Cav1.2 Ca2+ signaling at excitatory synapses.SIGNIFICANCE STATEMENT The number and localization of voltage-gated Cav Ca2+ channels are crucial determinants of neuronal excitability and synaptic transmission. We report that the protein densin-180 is highly enriched at excitatory synapses in the brain and enhances the cell surface trafficking and postsynaptic localization of Cav1.2 L-type Ca2+ channels in neurons. This interaction promotes coupling of Cav1.2 channels to activity-dependent gene transcription. Our results reveal a mechanism that may contribute to the roles of Cav1.2 in regulating cognition and mood.
| S-EPMC5426563 | biostudies-literature
Project description:BackgroundThe postnatal mammalian ovary undergoes a series of changes to ensure the maturation of sufficient follicles to support ovulation and fecundation over the reproductive life. It is well known that intracellular [Ca2+]i signals are necessary for ovulation, fertilization, and egg activation. However, we lack detailed knowledge of the molecular identity, cellular distribution, and functional role of Ca2+ channels expressed during folliculogenesis. In the neonatal period, ovarian maturation is controlled by protein growth factors released from the oocyte and granulosa cells. Conversely, during the early infantile period, maturation becomes gonadotropin-dependent and is controlled by granulosa and theca cells. The significance of intracellular Ca2+ signaling in folliculogenesis is supported by the observation that mice lacking the expression of Ca2+/calmodulin-dependent kinase IV in granulosa cells suffer abnormal follicular development and impaired fertility.ResultsUsing immunofluorescence in frozen ovarian sections and confocal microscopy, we assessed the expression of high-voltage activated Ca2+ channel alpha subunits and InsP3 and ryanodine receptors in the postnatal period from 3 to 16 days. During the neonatal stage, oocytes from primordial and primary follicles show high expression of various Ca2+-selective channels, with granulosa and stroma cells expressing significantly less. These channels are likely involved in supporting Ca2+-dependent secretion of peptide growth factors. In contrast, during the early and late infantile periods, Ca2+ channel expression in the oocyte diminishes, increasing significantly in the granulosa and particularly in immature theca cells surrounding secondary follicles.ConclusionsThe developmental switch of Ca2+ channel expression from the oocytes to the perifollicular cells likely reflects the vanishing role of the oocytes once granulosa and theca cells take control of folliculogenesis in response to gonadotropins acting on their receptors.
| S-EPMC9306205 | biostudies-literature
Project description:Voltage-gated Ca2+ (CaV) channels couple membrane depolarization to Ca2+ influx, triggering a range of Ca2+-dependent cellular processes. CaV channels are, therefore, crucial in shaping neuronal activity and function, depending on their individual temporal and spatial properties. Furthermore, many neurotransmitters and drugs that act through G protein coupled receptors (GPCRs), modulate neuronal activity by altering the expression, trafficking, or function of CaV channels. GPCR-dependent mechanisms that downregulate CaV channel expression levels are observed in many neurons but are, by comparison, less studied. Here we show that the growth hormone secretagogue receptor type 1a (GHSR), a GPCR, can inhibit the forwarding trafficking of several CaV subtypes, even in the absence of agonist. This constitutive form of GPCR inhibition of CaV channels depends on the presence of a CaVβ subunit. CaVβ subunits displace CaVα1 subunits from the endoplasmic reticulum. The actions of GHSR on CaV channels trafficking suggest a role for this signaling pathway in brain areas that control food intake, reward, and learning and memory.
| S-EPMC6518300 | biostudies-literature
Project description:During the recording of whole cell currents from stably transfected HEK-293 cells, the decline of currents carried by the recombinant human Cav2.3+β3 channel subunits is related to adenosine triphosphate (ATP) depletion after rupture of the cells. It reduces the number of functional channels and leads to a progressive shift of voltage-dependent gating to more negative potentials (Neumaier F., et al., 2018). Both effects can be counteracted by hydrolysable ATP, whose protective action is almost completely prevented by inhibition of serine/threonine but not tyrosine or lipid kinases. These findings indicate that ATP promotes phosphorylation of either the channel or an associated protein, whereas dephosphorylation during cell dialysis results in run-down. Protein phosphorylation is required for Cav2.3 channel function and could directly influence the normal features of current carried by these channels. Therefore, results from in vitro and in vivo phosphorylation of Cav2.3 are summarized to come closer to a functional analysis of structural variations in Cav2.3 splice variants.
| S-EPMC6986797 | biostudies-literature