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Gerald W. Zamponi - One of the best experts on this subject based on the ideXlab platform.

  • Neuronal Voltage-Gated Calcium Channels: Structure, Function, and DysFunction
    Neuron, 2014
    Co-Authors: Brett A. Simms, Gerald W. Zamponi
    Abstract:

    Voltage-gated Calcium Channels are the primary mediators of depolarization-induced Calcium entry into neurons. There is great diversity of Calcium Channel subtypes due to multiple genes that encode Calcium Channel α1 subunits, coassembly with a variety of ancillary Calcium Channel subunits, and alternative splicing. This allows these Channels to fulfill highly specialized roles in specific neuronal subtypes and at particular subcellular loci. While Calcium Channels are of critical importance to brain Function, their inappropriate expression or dysFunction gives rise to a variety of neurological disorders, including, pain, epilepsy, migraine, and ataxia. This Review discusses salient aspects of voltage-gated Calcium Channel Function, physiology, and pathophysiology.

  • advances in voltage gated Calcium Channel structure Function and physiology
    Biochimica et Biophysica Acta, 2013
    Co-Authors: Gerald W. Zamponi, Terrance P Snutch
    Abstract:

    It is well established that Calcium ions are important signalling molecules that mediate a wide range of physiological Functions, including muscle contraction, enzyme activation, and secretion. Excitable cells contain numerous pathways by which intracellular Calcium concentration can be elevated. Voltage-gated Calcium Channels are the primary mechanism of depolarization evoked Calcium entry into heart, muscle and brain cells. The mammalian genome expresses multiple Calcium Channel subtypes that fulfill specific cellular Functions. These Calcium Channels can either be monomers (as is the case with low voltage- activated T-type Calcium Channels), or multimeric protein complexes that are formed through the assembly of multiple Calcium Channels subunits (as for the high voltage-activated Calcium Channels). This special issue of BBA Biomembranes, focuses on some of the key roles of Calcium Channels, as well as aspects of Calcium Channel structure and modulation. In the lead off article, Dr. Diane Lipscombe discusses the role of alternate splicing in Calcium Channel Function. Most Calcium Channel subtypes are subject to regulation by alternate splicing mechanisms, and the resulting splice variants support specific cellular Functions. Dr. Jiang Yang then describes the regulation of high voltage-activated Calcium Channels by the ancillary Cavβ subunit. This subunit associates with the pore forming Cavα1 subunit of the Channel complex to not only regulate plasma membrane expression, but also Channel Function and modulation. Along these lines, Dr. Annette Dolphin discusses the role of the other major high voltage-activated Calcium Channel ancillary subunit – Cavα2δ – in membrane trafficking of the Channel complex, and as a target for the gabapentinoid pain therapeutics. Dr. Jin Tao then focuses on low voltage activated T-type Calcium Channels and their modulation by second messengers. T-type Calcium Channels play major roles in network synchrony and epilepsy as discussed byDrs.Hee-SupShinandSnutchintwoarticlesinthisissue. Inaddition, there is growing evidence that T-type Channels mal also control low threshold exocytosis, as described by Drs. Norbert Weiss and Zamponi. Dr. Kurt Beam leads off a series of articles concerning the Cav1 (L-type) Calcium Channel family. Dr. Beam summarizes the unique Functioning of the skeletal muscle Cav1.1L-type Channel. Dr. Alexandra Koschak then discusses how naturally occurring mutation in the Cav1 family provides novel insights into Calcium Channel structure and Function. Rounding out the L-type Channel segment, Dr. Emilio Carbone focuses on the roles of Cav1.2 and Cav1.3 Calcium Channels in chromaffin cells. The issue then moves towards N-type (Cav2.2) Calcium Channels. Dr. Adams provides a detailed overview of modulation of N-type Calcium Channels by peptide toxins isolated from fish hunting cone snails, and their therapeutic potential for chronic pain. Drs. Kevin Currie and Zamponi then provide a detailed account concerning the modulation of N-type Calcium Channels by G proteins and G protein coupled receptors, a field of long history and an example of deep insights into molecular mechanisms of Channel modulation. Dr. Henry Colecraft takes a broader view of high voltage activated Calcium Channel modulation by RGK proteins, a family of small G proteins that mediate a complex regulation of Calcium Channel activity. Finally, Dr. Daniela Pietrobon completes the issue by highlighting the role of Cav2.1 (P/Q-type) Calcium Channels in familial forms of migraine. In patients with this disorder naturally occurring mutations in the P/Q-type gene give rise to migraine phenotypes with varying degrees of severity. Clearly, this collection of reviews is only a snapshot of the many exciting findings in the Calcium Channel field. However, it provides a topical overview of pertinent topics in this area by some of the world's leading Calcium Channel researchers.

  • Voltage-Gated Calcium Channels
    2010
    Co-Authors: Gerald W. Zamponi
    Abstract:

    In response to changes in membrane potential, voltage-gated Calcium Channels mediate the influx of Calcium ions into many types of excitable and nonexcitable cells. Calcium flux subsequently regulates crucial physiological Functions, including neurotransmitter release, muscle contraction, Calcium-dependent enzyme and protein modulation, cell growth and differentiation, neuronal excitability, and Calcium-dependent gene transcription. The aberrant elevation of intracellular Calcium levels through altered Calcium Channel Function is related to a variety of serious human pathophysiological conditions, including cardiovascular disease, muscle disorders, acute and chronic pain, epilepsy, cerebellar ataxia, migraine, mood disorders, and certain types of cancer. To date, clinical agents blocking specific Calcium Channel subtypes have proven highly beneficial for the treatment of certain cardiovascular and neurological conditions.

  • Old proteins, developing roles: The regulation of Calcium Channels by synaptic proteins.
    Channels (Austin Tex.), 2008
    Co-Authors: Jonathan Davies, Gerald W. Zamponi
    Abstract:

    Coupling of presynaptic voltage-gated Calcium Channels to the synaptic release machinery is critical for neurotransmission. It was traditionally believed that anchoring Calcium Channels close to the Calcium microdomain dependent release machinery was the main reason for the physical interactions between Channels and synaptic proteins, however in recent years, it is becoming clear that these proteins additionally regulate Channel activity, and such processes as Channel targeting and alternative splicing, to orchestrate a much broader regulatory role in controlling Calcium Channel Function, Calcium influx and hence neurotransmission. Calcium signalling serves a multitude of cellular Functions and therefore requires tight regulation. Specific, often Calcium-dependent interactions between synaptic proteins and Calcium Channels appear to play a significant role in fine-tuning of the synaptic response over development. While it is clear that investigation of a few of the multitude of synaptic proteins will not provide a complete understanding of Calcium Channel regulation, consideration of the emerging mechanisms by which synaptic protein interactions might regulate Calcium Channel Function is important in order to understand their possible contributions to synaptic transmission. Here, we review the current state of knowledge of the molecular mechanisms by which synaptic proteins regulate presynaptic Calcium Channel activity.

  • Uncoupling of Calcium Channel α1 and β Subunits in Developing Neurons
    The Journal of biological chemistry, 2004
    Co-Authors: J. David Spafford, Jan Van Minnen, Peter H. Larsen, August B. Smit, Naweed I. Syed, Gerald W. Zamponi
    Abstract:

    Abstract Calcium Channel β subunits are key modulators of Calcium Channel Function and membrane targeting of the pore-forming α1 subunit. Here we show that an invertebrate (Lymnaea stagnalis) homolog of P/Q- and N-type Calcium Channels (LCav2), although colocalized with β subunits in synapses of mature neurons, is physically uncoupled from the β subunits in the leading edge of growth cones of outgrowing neurons. Moreover, LCav2 Channels that mediate transmitter release in mature synapses also participate in neuronal outgrowth in growth cones. The differential association of β subunits with synaptic Calcium Channels and those expressed in emergent neuronal growth suggests that β subunits may play a role in the transformation of Cav2 Calcium Channel Function in immature neurons and mature synapses.

D L Minor - One of the best experts on this subject based on the ideXlab platform.

  • Apo States of Calmodulin and CaBP1 Control CaV1 Voltage-Gated Calcium Channel Function through Direct Competition for the IQ Domain
    Journal of molecular biology, 2013
    Co-Authors: Felix Findeisen, C.h. Rumpf, D L Minor
    Abstract:

    In neurons, binding of calmodulin (CaM) or Calcium-binding protein 1 (CaBP1) to the CaV1 (L-type) voltage-gated Calcium Channel IQ domain endows the Channel with diametrically opposed properties. CaM causes Calcium-dependent inactivation and limits Calcium entry, whereas CaBP1 blocks Calcium-dependent inactivation (CDI) and allows sustained Calcium influx. Here, we combine isothermal titration calorimetry with cell-based Functional measurements and mathematical modeling to show that these Calcium sensors behave in a competitive manner that is explained quantitatively by their apo-state binding affinities for the IQ domain. This competition can be completely blocked by covalent tethering of CaM to the Channel. Further, we show that Ca(2+)/CaM has a sub-picomolar affinity for the IQ domain that is achieved without drastic alteration of Calcium-binding properties. The observation that the apo forms of CaM and CaBP1 compete with each other demonstrates a simple mechanism for direct modulation of CaV1 Function and suggests a means by which excitable cells may dynamically tune CaV activity.

  • The structural biology of voltage-gated Calcium Channel Function and regulation
    Biochemical Society Transactions, 2006
    Co-Authors: F Van Petegem, D L Minor
    Abstract:

    Voltage-gated Calcium Channels (CaVs) are large (~0.5 MDa), multisubunit, macromolecular machines that control Calcium entry into cells in response to membrane potential changes. These molecular switches play pivotal roles in cardiac action potentials, neurotransmitter release, muscle contraction, Calcium-dependent gene transcription and synaptic transmission. CaVs possess self-regulatory mechanisms that permit them to change their behaviour in response to activity, including voltage-dependent inactivation, Calcium-dependent inactivation and Calcium-dependent facilitation. These processes arise from the concerted action of different Channel domains with CaV β-subunits and the soluble Calcium sensor calmodulin. Until recently, nothing was known about the CaV structure at high resolution. Recent crystallographic work has revealed the first glimpses at the CaV molecular framework and set a new direction towards a detailed mechanistic understanding of CaV Function.

  • The structural biology of voltage-gated Calcium Channel Function and regulation.
    Biochemical Society transactions, 2006
    Co-Authors: F Van Petegem, D L Minor
    Abstract:

    Voltage-gated Calcium Channels (CaVs) are large (approximately 0.5 MDa), multisubunit, macromolecular machines that control Calcium entry into cells in response to membrane potential changes. These molecular switches play pivotal roles in cardiac action potentials, neurotransmitter release, muscle contraction, Calcium-dependent gene transcription and synaptic transmission. CaVs possess self-regulatory mechanisms that permit them to change their behaviour in response to activity, including voltage-dependent inactivation, Calcium-dependent inactivation and Calcium-dependent facilitation. These processes arise from the concerted action of different Channel domains with CaV beta-subunits and the soluble Calcium sensor calmodulin. Until recently, nothing was known about the CaV structure at high resolution. Recent crystallographic work has revealed the first glimpses at the CaV molecular framework and set a new direction towards a detailed mechanistic understanding of CaV Function.

Shaun L. Sandow - One of the best experts on this subject based on the ideXlab platform.

  • Enhanced contractility in pregnancy is associated with augmented TRPC3, L-type, and T-type voltage-dependent Calcium Channel Function in rat uterine radial artery
    American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2013
    Co-Authors: Sevvandi Senadheera, Paul P. Bertrand, T. Hilton Grayson, Leo R. Leader, Marianne Tare, Timothy V. Murphy, Shaun L. Sandow
    Abstract:

    In pregnancy, α-adrenoceptor-mediated vasoconstriction is augmented in uterine radial arteries and is accompanied by underlying changes in smooth muscle (SM) Ca2+ activity. This study aims to deter...

  • Enhanced contractility in pregnancy is associated with augmented TRPC3, L-type, and T-type voltage-dependent Calcium Channel Function in rat uterine radial artery.
    American journal of physiology. Regulatory integrative and comparative physiology, 2013
    Co-Authors: Sevvandi Senadheera, Paul P. Bertrand, T. Hilton Grayson, Marianne Tare, Timothy V. Murphy, Leo Leader, Shaun L. Sandow
    Abstract:

    In pregnancy, α-adrenoceptor-mediated vasoconstriction is augmented in uterine radial arteries and is accompanied by underlying changes in smooth muscle (SM) Ca(2+) activity. This study aims to determine the Ca(2+) entry Channels associated with altered vasoconstriction in pregnancy, with the hypothesis that augmented vasoconstriction involves transient receptor potential canonical type-3 (TRPC3) and L- and T-type voltage-dependent Ca(2+) Channels. Immunohistochemistry showed TRPC3, L-type Cav1.2 (as the α1C subunit), T-type Cav3.1 (α1G), and Cav3.2 (α1H) localization to the uterine radial artery SM. Fluorescence intensity of TRPC3, Cav1.2, and Cav3.2 was increased, and Cav3.1 decreased in radial artery SM from pregnant rats. Western blot analysis confirmed increased TRPC3 protein expression in the radial artery from pregnant rats. Pressure myography incorporating pharmacological intervention to examine the role of these Channels in uterine radial arteries showed an attenuation of phenylephrine (PE)-induced constriction with Pyr3 {1-[4-[(2,3,3-trichloro-1-oxo-2-propen-1-yl)amino]phenyl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid}-mediated TRPC3 inhibition or with nifedipine-mediated L-type Channel block alone in vessels from pregnant rats; both effects of which were diminished in radial arteries from nonpregnant rats. Combined TRPC3 and L-type inhibition attenuated PE-induced constriction in radial arteries, and the residual vasoconstriction was reduced and abolished with T-type Channel block with NNC 55-0396 in arteries from nonpregnant and pregnant rats, respectively. With SM Ca(2+) stores depleted and in the presence of PE, nifedipine, and NNC 55-0396, blockade of TRPC3 reversed PE-induced constriction. These data suggest that TRPC3 Channels act synergistically with L- and T-type Channels to modulate radial artery vasoconstriction, with the mechanism being augmented in pregnancy.

Sevvandi Senadheera - One of the best experts on this subject based on the ideXlab platform.

  • Enhanced contractility in pregnancy is associated with augmented TRPC3, L-type, and T-type voltage-dependent Calcium Channel Function in rat uterine radial artery
    American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2013
    Co-Authors: Sevvandi Senadheera, Paul P. Bertrand, T. Hilton Grayson, Leo R. Leader, Marianne Tare, Timothy V. Murphy, Shaun L. Sandow
    Abstract:

    In pregnancy, α-adrenoceptor-mediated vasoconstriction is augmented in uterine radial arteries and is accompanied by underlying changes in smooth muscle (SM) Ca2+ activity. This study aims to deter...

  • Enhanced contractility in pregnancy is associated with augmented TRPC3, L-type, and T-type voltage-dependent Calcium Channel Function in rat uterine radial artery.
    American journal of physiology. Regulatory integrative and comparative physiology, 2013
    Co-Authors: Sevvandi Senadheera, Paul P. Bertrand, T. Hilton Grayson, Marianne Tare, Timothy V. Murphy, Leo Leader, Shaun L. Sandow
    Abstract:

    In pregnancy, α-adrenoceptor-mediated vasoconstriction is augmented in uterine radial arteries and is accompanied by underlying changes in smooth muscle (SM) Ca(2+) activity. This study aims to determine the Ca(2+) entry Channels associated with altered vasoconstriction in pregnancy, with the hypothesis that augmented vasoconstriction involves transient receptor potential canonical type-3 (TRPC3) and L- and T-type voltage-dependent Ca(2+) Channels. Immunohistochemistry showed TRPC3, L-type Cav1.2 (as the α1C subunit), T-type Cav3.1 (α1G), and Cav3.2 (α1H) localization to the uterine radial artery SM. Fluorescence intensity of TRPC3, Cav1.2, and Cav3.2 was increased, and Cav3.1 decreased in radial artery SM from pregnant rats. Western blot analysis confirmed increased TRPC3 protein expression in the radial artery from pregnant rats. Pressure myography incorporating pharmacological intervention to examine the role of these Channels in uterine radial arteries showed an attenuation of phenylephrine (PE)-induced constriction with Pyr3 {1-[4-[(2,3,3-trichloro-1-oxo-2-propen-1-yl)amino]phenyl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid}-mediated TRPC3 inhibition or with nifedipine-mediated L-type Channel block alone in vessels from pregnant rats; both effects of which were diminished in radial arteries from nonpregnant rats. Combined TRPC3 and L-type inhibition attenuated PE-induced constriction in radial arteries, and the residual vasoconstriction was reduced and abolished with T-type Channel block with NNC 55-0396 in arteries from nonpregnant and pregnant rats, respectively. With SM Ca(2+) stores depleted and in the presence of PE, nifedipine, and NNC 55-0396, blockade of TRPC3 reversed PE-induced constriction. These data suggest that TRPC3 Channels act synergistically with L- and T-type Channels to modulate radial artery vasoconstriction, with the mechanism being augmented in pregnancy.

Stefan Herzig - One of the best experts on this subject based on the ideXlab platform.

  • Rare Mutations of CACNB2 Found in Autism Spectrum Disease-Affected Families Alter Calcium Channel Function
    PloS one, 2014
    Co-Authors: Alexandra F. Breitenkamp, Jan Matthes, Robert D. Nass, Judith Sinzig, Gerd Lehmkuhl, Peter Nürnberg, Stefan Herzig
    Abstract:

    Autism Spectrum Disorders (ASD) are complex neurodevelopmental diseases clinically defined by dysFunction of social interaction. Dysregulation of cellular Calcium homeostasis might be involved in ASD pathogenesis, and genes coding for the L-type Calcium Channel subunits CaV1.2 (CACNA1C) and CaVβ2 (CACNB2) were recently identified as risk loci for psychiatric diseases. Here, we present three rare missense mutations of CACNB2 (G167S, S197F, and F240L) found in ASD-affected families, two of them described here for the first time (G167S and F240L). All these mutations affect highly conserved regions while being absent in a sample of ethnically matched controls. We suggest the mutations to be of physiological relevance since they modulate whole-cell Ba2+ currents through Calcium Channels when expressed in a recombinant system (HEK-293 cells). Two mutations displayed significantly decelerated time-dependent inactivation as well as increased sensitivity of voltage-dependent inactivation. In contrast, the third mutation (F240L) showed significantly accelerated time-dependent inactivation. By altering the kinetic parameters, the mutations are reminiscent of the CACNA1C mutation causing Timothy Syndrome, a Mendelian disease presenting with ASD. In conclusion, the results of our first-time biophysical characterization of these three rare CACNB2 missense mutations identified in ASD patients support the hypothesis that Calcium Channel dysFunction may contribute to autism.

  • Calcium Channel Function and regulation in β_1- and β_2-adrenoceptor transgenic mice
    Naunyn-Schmiedeberg's Archives of Pharmacology, 2004
    Co-Authors: Katharina Foerster, Tomas Kaeferstein, Ferdi Groner, Stefan Engelhardt, Jan Matthes, Walter J. Koch, Martin J. Lohse, Stefan Herzig
    Abstract:

    Cardiac effects of catecholamines on the L-type Calcium Channel depend on β-adrenoceptor subtype (β_1- vs. β_2-adrenoceptor). Chronic overexpression of these receptors leads to hypertrophy and early death at moderate (β_1) or excessive (β_2) levels of overexpression respectively. In order to examine the role of L-type Calcium Channels in altered cardiomyocyte Calcium homeostasis found with β_1-adrenoceptor overexpression, and to understand the quantitative differences between β-adrenoceptor subtypes regarding Calcium Channel regulation, we examined single Channels in myocytes obtained from β_1- and β_2-adrenoceptor transgenic mice. The effects of the agonist isoproterenol were investigated and compared with acute receptor stimulation in the respective non-transgenic littermates. Channels from β_1-adrenoceptor transgenic mice have normal baseline activity, and Channel number is not reduced. This contrasts to previous findings with β_2-adrenoceptor transgenic mice, where Channel activity is depressed. Isoproterenol is unable to stimulate Channel activity in both transgenic models. In conclusion, the L-type Calcium Channel is not likely to be involved in alterations of Calcium handling of β_1-adrenoceptor transgenic myocytes. Furthermore, chronic β_1-adrenoceptor overexpression does not depress Channel activity, giving another example of the difference between β_1- and β_2-adrenoceptor signal transduction.

  • Calcium Channel Function and regulation in β1- and β2-adrenoceptor transgenic mice
    Naunyn-Schmiedeberg's archives of pharmacology, 2004
    Co-Authors: Katharina Foerster, Tomas Kaeferstein, Ferdi Groner, Stefan Engelhardt, Jan Matthes, Walter J. Koch, Martin J. Lohse, Stefan Herzig
    Abstract:

    Cardiac effects of catecholamines on the L-type Calcium Channel depend on β-adrenoceptor subtype (β1- vs. β2-adrenoceptor). Chronic overexpression of these receptors leads to hypertrophy and early death at moderate (β1) or excessive (β2) levels of overexpression respectively. In order to examine the role of L-type Calcium Channels in altered cardiomyocyte Calcium homeostasis found with β1-adrenoceptor overexpression, and to understand the quantitative differences between β-adrenoceptor subtypes regarding Calcium Channel regulation, we examined single Channels in myocytes obtained from β1- and β2-adrenoceptor transgenic mice. The effects of the agonist isoproterenol were investigated and compared with acute receptor stimulation in the respective non-transgenic littermates.