Molecular physiology of voltage-gated Ca2+ channels

Summary

Principal Investigator: Jian Yang
Abstract: DESCRIPTION (provided by applicant): Voltage-gated calcium channels (VGCCs) control and regulate numerous physiological processes, ranging from muscle contraction, heartbeat, neural communication and hormone secretion to cell differentiation, motility, growth and death. As such, their activity is tightly regulated by diverse molecules and pathways, including protein kinases and phosphatases, G proteins, calcium and calmodulin, SNAREs, and phospholipids. We have uncovered a new paradigm for VGCC regulation: The pore-forming a1 subunit of neuronal surface L-type VGCCs is proteolytically cleaved in the cytoplasmic loops (mainly the II-III loop but also the I-II loop) connecting the four homologous repeats, this cleavage is activity-dependent, and the cleaved fragments (called hemi-channels) physically separate. This novel form of channel regulation may significantly impact L-type calcium channel activity, calcium signaling, and gene transcription in neurons. We propose to study the signaling molecules and pathways, the dynamics, and the functional consequences of mid-channel proteolysis, and the fate and function of the resulting hemi-channels, using a combination of biochemistry, proteomics, fixed cell and live cell imaging, and electrophysiology. As intracellular calcium signaling is severely altered in aging neurons and age-related neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, we will investigate whether mid-channel proteolysis and hemi-channel separation are perturbed in these physiological and pathological processes. We will also expand our studies to N- and P/Q-type calcium channels, which mediate neurotransmitter release. These studies will provide mechanistic insights into a hitherto ill-studied form of VGCC regulation and may lead to the development of new therapeutic strategies for calcium homeostasis-related diseases. PUBLIC HEALTH RELEVANCE: Voltage-gated calcium channels (VGCCs) are essential for human physiology. Their mutations and malfunction cause a variety of diseases, including epilepsy, ataxia, cardiovascular diseases, and autism. By studying a novel form of activity-dependent fragmentation of VGCCs on the cell membrane, this work may lead to a better understanding of VGCC function and regulation in physiological and pathological conditions.
Funding Period: 2005-12-01 - 2016-04-30
more information: NIH RePORT

Top Publications

  1. pmc Origin of the voltage dependence of G-protein regulation of P/Q-type Ca2+ channels
    Yun Zhang
    Department of Biological Sciences, Columbia University, New York, New York 10027, USA
    J Neurosci 28:14176-88. 2008
  2. pmc Not very funny: how a single mutation causes heritable bradycardia
    Zafir Buraei
    Deparment of Biology and Health Sciences, Pace University, New York, NY 10038, USA
    Structure 20:1991-2. 2012
  3. ncbi Regulation of voltage-gated calcium channels by proteolysis
    Kathryn Abele
    Department of Biological Sciences, Columbia University, New York, NY 10027, USA
    Sheng Li Xue Bao 64:504-14. 2012
  4. pmc Structure and function of the β subunit of voltage-gated Ca²⁺ channels
    Zafir Buraei
    Department of Biological Sciences, Columbia University, New York, NY 10027, USA
    Biochim Biophys Acta 1828:1530-40. 2013
  5. pmc Molecular determinants of Gem protein inhibition of P/Q-type Ca2+ channels
    Mingming Fan
    Department of Biological Sciences, Columbia University, New York, New York 10027, USA
    J Biol Chem 287:22749-58. 2012
  6. ncbi The ß subunit of voltage-gated Ca2+ channels
    Zafir Buraei
    Department of Biological Sciences, Columbia University, New York, NY 10027, USA
    Physiol Rev 90:1461-506. 2010
  7. pmc Direct inhibition of P/Q-type voltage-gated Ca2+ channels by Gem does not require a direct Gem/Cavbeta interaction
    Mingming Fan
    Department of Biological Sciences, Columbia University, New York, NY 10027, USA
    Proc Natl Acad Sci U S A 107:14887-92. 2010
  8. pmc The beta subunit of voltage-gated Ca2+ channels interacts with and regulates the activity of a novel isoform of Pax6
    Yun Zhang
    Department of Biological Sciences, Columbia University, New York, New York 10027, USA
    J Biol Chem 285:2527-36. 2010
  9. pmc Functional dissection of the intramolecular Src homology 3-guanylate kinase domain coupling in voltage-gated Ca2+ channel beta-subunits
    Yu hang Chen
    Department of Biological Sciences, 917 Fairchild Center, MC2462, Columbia University, New York, NY 10027, USA
    FEBS Lett 583:1969-75. 2009
  10. pmc Age-related homeostatic midchannel proteolysis of neuronal L-type voltage-gated Ca²⁺ channels
    Ioannis E Michailidis
    Department of Biological Sciences, Columbia University, New York, NY 10027, USA
    Neuron 82:1045-57. 2014

Research Grants

  1. Activation of Phospholipase Cbeta by G Proteins
    SUZANNE F SCARLATA; Fiscal Year: 2013
  2. DYNAMICS OF SIGNAL TRANSDUCTION IN NEURONS
    Roger Y Tsien; Fiscal Year: 2013
  3. Endogenous Cannabinoids and Brain Function
    Aron H Lichtman; Fiscal Year: 2013
  4. Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration
    Jeffery W Kelly; Fiscal Year: 2013
  5. Vermont Center on Behavior and Health
    Stephen T Higgins; Fiscal Year: 2013
  6. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
  7. Structure and Function of Neurotransmitter Transporters
    Harel Weinstein; Fiscal Year: 2013
  8. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
  9. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
  10. Alerations of Sleep and Circadian Timing in Aging
    Eve Van Cauter; Fiscal Year: 2013

Detail Information

Publications10

  1. pmc Origin of the voltage dependence of G-protein regulation of P/Q-type Ca2+ channels
    Yun Zhang
    Department of Biological Sciences, Columbia University, New York, New York 10027, USA
    J Neurosci 28:14176-88. 2008
    ....
  2. pmc Not very funny: how a single mutation causes heritable bradycardia
    Zafir Buraei
    Deparment of Biology and Health Sciences, Pace University, New York, NY 10038, USA
    Structure 20:1991-2. 2012
    ..In this issue of Structure, Xu and colleagues reveal that an arrhythmia-causing mutation of an HCN channel weakens cAMP binding to the channel by altering the local structure of its entry-exit pathway...
  3. ncbi Regulation of voltage-gated calcium channels by proteolysis
    Kathryn Abele
    Department of Biological Sciences, Columbia University, New York, NY 10027, USA
    Sheng Li Xue Bao 64:504-14. 2012
    ..Truncated forms of N-type channel Ca(v)α(1), generated by mutagenesis, affect the expression of full-length channels. New forms of proteolysis of VGCC subunits remain to be discovered and may represent a fruitful area of VGCC research...
  4. pmc Structure and function of the β subunit of voltage-gated Ca²⁺ channels
    Zafir Buraei
    Department of Biological Sciences, Columbia University, New York, NY 10027, USA
    Biochim Biophys Acta 1828:1530-40. 2013
    ..In this article, we review the structure and various biological functions of Ca(v)β, as well as recent advances. This article is part of a Special Issue entitled: Calcium channels...
  5. pmc Molecular determinants of Gem protein inhibition of P/Q-type Ca2+ channels
    Mingming Fan
    Department of Biological Sciences, Columbia University, New York, New York 10027, USA
    J Biol Chem 287:22749-58. 2012
    ..These results suggest that Gem contains two candidate inhibitory sites, each capable of producing full inhibition of P/Q-type Ca(2+) channels...
  6. ncbi The ß subunit of voltage-gated Ca2+ channels
    Zafir Buraei
    Department of Biological Sciences, Columbia University, New York, NY 10027, USA
    Physiol Rev 90:1461-506. 2010
    ..In this article, we review the structure and various biological functions of Ca(v)β, with both a historical perspective as well as an emphasis on recent advances...
  7. pmc Direct inhibition of P/Q-type voltage-gated Ca2+ channels by Gem does not require a direct Gem/Cavbeta interaction
    Mingming Fan
    Department of Biological Sciences, Columbia University, New York, NY 10027, USA
    Proc Natl Acad Sci U S A 107:14887-92. 2010
    ....
  8. pmc The beta subunit of voltage-gated Ca2+ channels interacts with and regulates the activity of a novel isoform of Pax6
    Yun Zhang
    Department of Biological Sciences, Columbia University, New York, New York 10027, USA
    J Biol Chem 285:2527-36. 2010
    ..These results suggest that full-length Ca(v)beta may act directly as a transcription regulator independent of its role in regulating Ca(2+) channel activity...
  9. pmc Functional dissection of the intramolecular Src homology 3-guanylate kinase domain coupling in voltage-gated Ca2+ channel beta-subunits
    Yu hang Chen
    Department of Biological Sciences, 917 Fairchild Center, MC2462, Columbia University, New York, NY 10027, USA
    FEBS Lett 583:1969-75. 2009
    ..Alterations of these elements uncouple the two functions of the beta-subunit, degrading its ability to regulate gating while leaving its chaperone effect intact...
  10. pmc Age-related homeostatic midchannel proteolysis of neuronal L-type voltage-gated Ca²⁺ channels
    Ioannis E Michailidis
    Department of Biological Sciences, Columbia University, New York, NY 10027, USA
    Neuron 82:1045-57. 2014
    ....

Research Grants30

  1. Activation of Phospholipase Cbeta by G Proteins
    SUZANNE F SCARLATA; Fiscal Year: 2013
    ..Importantly, the link between PLC2 and synucleins in promoting neurodegenerative disease and breast cancer will be explored to develop more effective therapeutics. ..
  2. DYNAMICS OF SIGNAL TRANSDUCTION IN NEURONS
    Roger Y Tsien; Fiscal Year: 2013
    ..Such tools will help elucidate mechanisms of neuronal information processing, communication, lifecycles, control of behavior, and pathological injury. ..
  3. Endogenous Cannabinoids and Brain Function
    Aron H Lichtman; Fiscal Year: 2013
    ..Ultimately, the knowledge gained from this basic research will yield novel therapeutic targets that can be exploited with the pharmacological agents developed here. PROGRAM CHARACTERISTICS ..
  4. Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration
    Jeffery W Kelly; Fiscal Year: 2013
    ..abstract_text> ..
  5. Vermont Center on Behavior and Health
    Stephen T Higgins; Fiscal Year: 2013
    ..S. public health. ..
  6. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  7. Structure and Function of Neurotransmitter Transporters
    Harel Weinstein; Fiscal Year: 2013
    ....
  8. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  9. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  10. Alerations of Sleep and Circadian Timing in Aging
    Eve Van Cauter; Fiscal Year: 2013
    ..Core B (Methods and Analysis) will standard operating procedures for data collection, archival and analysis. Core C will assay peripheral levels of hormones, cytokines and other blood constituents. ..
  11. A Gene therapeutic approach to stable suppression of HIV-1 replication
    MICHAEL R FARZAN; Fiscal Year: 2013
    ..These studies will establish principles and protocols directly applicable to subsequent human clinical trials. ..
  12. Mechanisms of Central Neuron Synaptogenesis
    ANN M CRAIG; Fiscal Year: 2013
    ....