INTERCELLULAR COMMUNICATION IN THE LENS

Summary

Principal Investigator: Miduturu Srinivas
Abstract: Abstract Gap junctional communication provided by connexin channels is required for postnatal lens growth and transparency. Targeted deletions of genes encoding Cx46 and Cx50 lead to cataracts in mice. Similarly, mutations in both Cx50 and Cx46 genes cause a variety of cataract types in both humans and mice. Alterations in coupling have been suggested to underlie cataracts that occur with diabetes and with age, but there are few studies directly linking gap junctional coupling to these pathophysiological conditions. More recently, we found that there are differences in the molecular permeability through channels made of Cx46, Cx50 and Cx43. In this proposal, we will continue to pursue electrophysiological studies to understand how the diversity in channel types formed by connexin proteins influences lens function and how their alteration leads to congenital and age-related cataracts by pursuing the following two Aims. In Aim 1, we will determine the importance of coupling provided by Cx46 and Cx50 gap junctions in the lens in the maintenance of adequate concentrations of important metabolites in inner fiber cells. We will use electrophysiological and biochemical assays to study the permeation of molecules in vitro and in vivo. We will also determine whether Cx50 and Cx46 mutations that cause congenital cataracts have alterations in molecular permeability. Second, we will determine whether coupling conductance and/or permeability is altered with aging and oxidative stress. Mass spectrometric methods will be employed to identify modifications to connexins with aging and during cataractogenesis. The effect of modifications on conductance and permeability of gap junctions will be assessed using electrophysiological methods.
Funding Period: 2002-02-01 - 2015-07-31
more information: NIH RePORT

Top Publications

  1. pmc Regulation of connexin hemichannels by monovalent cations
    Miduturu Srinivas
    State University of New York College of Optometry, New York, NY 10036, USA
    J Gen Physiol 127:67-75. 2006
  2. pmc The D50N mutation and syndromic deafness: altered Cx26 hemichannel properties caused by effects on the pore and intersubunit interactions
    Helmuth A Sánchez
    Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    J Gen Physiol 142:3-22. 2013
  3. pmc Connexin channel modulators and their mechanisms of action
    Vytas K Verselis
    Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Neuropharmacology 75:517-24. 2013
  4. pmc The N-terminal half of the connexin protein contains the core elements of the pore and voltage gates
    Jack Kronengold
    Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA
    J Membr Biol 245:453-63. 2012
  5. pmc Triarylmethanes, a new class of cx50 inhibitors
    Silke B Bodendiek
    Department of Pharmacology, University of California Davis, CA, USA
    Front Pharmacol 3:106. 2012
  6. pmc Mechanism of inhibition of connexin channels by the quinine derivative N-benzylquininium
    Clio Rubinos
    Department of Biological Sciences, SUNY College of Optometry, New York, NY 10036, USA
    J Gen Physiol 139:69-82. 2012
  7. pmc Interaction between Connexin50 and mitogen-activated protein kinase signaling in lens homeostasis
    Teresa I Shakespeare
    Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794 8661, USA
    Mol Biol Cell 20:2582-92. 2009
  8. pmc Loop gating of connexin hemichannels involves movement of pore-lining residues in the first extracellular loop domain
    Vytas K Verselis
    Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    J Biol Chem 284:4484-93. 2009
  9. pmc Divalent cations regulate connexin hemichannels by modulating intrinsic voltage-dependent gating
    Vytas K Verselis
    Albert Einstein College of Medicine, Bronx, NY 10561, USA
    J Gen Physiol 132:315-27. 2008
  10. ncbi Optimal lens epithelial cell proliferation is dependent on the connexin isoform providing gap junctional coupling
    Thomas W White
    Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York, USA
    Invest Ophthalmol Vis Sci 48:5630-7. 2007

Detail Information

Publications13

  1. pmc Regulation of connexin hemichannels by monovalent cations
    Miduturu Srinivas
    State University of New York College of Optometry, New York, NY 10036, USA
    J Gen Physiol 127:67-75. 2006
    ..Our results demonstrate a new, robust means of regulating hemichannels through a combination of extracellular monovalent and divalent cations, principally Na+, K+, and Ca2+...
  2. pmc The D50N mutation and syndromic deafness: altered Cx26 hemichannel properties caused by effects on the pore and intersubunit interactions
    Helmuth A Sánchez
    Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    J Gen Physiol 142:3-22. 2013
    ..Collectively, these data provide insight into Cx26 structure-function and the underlying bases for the phenotypes associated with KID syndrome patients carrying the D50N mutation. ..
  3. pmc Connexin channel modulators and their mechanisms of action
    Vytas K Verselis
    Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Neuropharmacology 75:517-24. 2013
    ..This article is part of the Special Issue Section entitled 'Current Pharmacology of Gap Junction Channels and Hemichannels'. ..
  4. pmc The N-terminal half of the connexin protein contains the core elements of the pore and voltage gates
    Jack Kronengold
    Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA
    J Membr Biol 245:453-63. 2012
    ....
  5. pmc Triarylmethanes, a new class of cx50 inhibitors
    Silke B Bodendiek
    Department of Pharmacology, University of California Davis, CA, USA
    Front Pharmacol 3:106. 2012
    ..In addition, our results indicate that a similar approach may be used to find specific inhibitors of other connexin subtypes...
  6. pmc Mechanism of inhibition of connexin channels by the quinine derivative N-benzylquininium
    Clio Rubinos
    Department of Biological Sciences, SUNY College of Optometry, New York, NY 10036, USA
    J Gen Physiol 139:69-82. 2012
    ..Collectively, these data suggest a mechanism of action for BQ(+) that involves modulation loop gating rather than channel block as a result of binding in the NT domain...
  7. pmc Interaction between Connexin50 and mitogen-activated protein kinase signaling in lens homeostasis
    Teresa I Shakespeare
    Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794 8661, USA
    Mol Biol Cell 20:2582-92. 2009
    ..These results indicate that MAPK signaling specifically modulates coupling mediated by Cx50 and that gap junctional communication and signal transduction pathways may interact in osmotic regulation during postnatal fiber development...
  8. pmc Loop gating of connexin hemichannels involves movement of pore-lining residues in the first extracellular loop domain
    Vytas K Verselis
    Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    J Biol Chem 284:4484-93. 2009
    ..These results indicate that metal ions access the cysteine side chains through the open pore and that closure of the loop gate involves movement of the TM1/E1 region that results in local narrowing of the large aqueous connexin pore...
  9. pmc Divalent cations regulate connexin hemichannels by modulating intrinsic voltage-dependent gating
    Vytas K Verselis
    Albert Einstein College of Medicine, Bronx, NY 10561, USA
    J Gen Physiol 132:315-27. 2008
    ..Thus, we demonstrate that both forms of voltage dependence are intrinsic gating mechanisms in Cx46 hemichannels and that the action of external divalent cations is to selectively modulate loop gating...
  10. ncbi Optimal lens epithelial cell proliferation is dependent on the connexin isoform providing gap junctional coupling
    Thomas W White
    Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York, USA
    Invest Ophthalmol Vis Sci 48:5630-7. 2007
    ..To determine which connexins functionally contribute to epithelial cell coupling and proliferation, junctional coupling from epithelial cells of wild-type and knockin mice was examined...
  11. ncbi Mefloquine effects on the lens suggest cooperative gating of gap junction channels
    Francisco J Martinez-Wittinghan
    Department of Physiology and Biophysics, State University of New York, Stony Brook, NY 11794 8661, USA
    J Membr Biol 211:163-71. 2006
    ..These results suggest the two types of channels interact and gate cooperatively...
  12. ncbi Block of specific gap junction channel subtypes by 2-aminoethoxydiphenyl borate (2-APB)
    Donglin Bai
    Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
    J Pharmacol Exp Ther 319:1452-8. 2006
    ..The differential efficacy of block by 2-APB of gap junction channels formed by different connexins may provide a useful tool that could be exploited in gap junction research to selectively block certain gap junction channel subtypes...
  13. pmc Functional effects of Cx50 mutations associated with congenital cataracts
    Clio Rubinos
    Department of Biological and Vision Sciences and the Graduate Center for Vision Research, State University of New York College of Optometry, New York, New York and
    Am J Physiol Cell Physiol 306:C212-20. 2014
    ..These results suggest that unique interactions between mutant and wild-type lens connexins might underlie the development of various cataract phenotypes in humans. ..

Research Grants30

  1. Mitochondrial Dysfunction in Neurodegeneration of Aging
    Gary E Gibson; Fiscal Year: 2013
    ..Successful completion of the goals of these projects can be expected to provide new insights into neurodegenerative processes and contribute to novel approaches to ameliorating age-related neurodegenerations. ..
  2. Mechanistic Studies of Alkyl Hydroperoxide Reductase and Related Redox Proteins
    Leslie B Poole; Fiscal Year: 2013
    ....
  3. BIOLOGY OF LENS INTERCELLULAR COMMUNICATION
    Eric C Beyer; Fiscal Year: 2013
    ..abstract_text> ..
  4. Transcriptional control of the mouse aA-crystallin locus
    Ales Cvekl; Fiscal Year: 2013
    ....
  5. ELECTROLYTE AND FLUID TRANSPORT IN OCULAR MEMBRANES
    Oscar A Candia; Fiscal Year: 2013
    ..Advancing our knowledge of normal lens function is essential for the future development of potential anti-cataract and presbyopia therapies. ..
  6. TOXIC SUBSTANCES IN THE ENVIRONMENT
    Martyn T Smith; Fiscal Year: 2013
    ..The program will be overseen and coordinated by an Administration core (A). ..
  7. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  8. Lens intercellular communication connexins and cataract
    Thomas W White; Fiscal Year: 2013
    ..They also will broaden the general paradigm of how an integrated system of intercellular communication contributes to the regulation of development in many tissues. ..
  9. Conformation and Dynamics of Cataract Mutants of human gammaD crystallin
    Angela M Gronenborn; Fiscal Year: 2013
    ..This will prepare the basis for discovering small molecule inhibitors of aggregation, an approach that has already yielded some results in a number of neurodegenerative protein deposition diseases. ..
  10. Homeostatic Roles of Connexin43 in Response to DNA Damage
    DANNY SAM ROH; Fiscal Year: 2013
    ..This proposal studies a potential coping mechanism to DNA damage that involves changes in how damaged cells communicate with one another to maintain their function and viability. ..
  11. Molecular Analysis of Microdissected Human Lenses
    Marc Kantorow; Fiscal Year: 2013
    ..The information gained from this work will have a major impact on the rational design of therapeutics that could prevent cataract formation. ..
  12. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
    ..The ultimate goal of all the proposed studies is to define the molecular events that feature in the formation of human prions in order to develop therapeutics that cure the human prion diseases. ..
  13. Cadiorenal and Metabolic Diseases Research Center
    John E Hall; Fiscal Year: 2013
    ..abstract_text> ..
  14. STRUCTURE AND DYNAMICS OF CONNEXIN26 GAP JUNCTIONS
    Gina E Sosinsky; Fiscal Year: 2013
    ..The proposed research is significant because results will be useful in defining better drugs and other therapeutics that potentially ameliorate connexin-related diseases. ..
  15. AMINO-CARBONYL REACTIONS IN THE AGING HUMAN LENS
    Vincent M Monnier; Fiscal Year: 2013
    ..To achieve these goals we will use powerful techniques that combine laser capture microdissection, proteomics and dynamic light scattering (DLS). ..
  16. Role of Aquaporin-0 for cell-to-cell adhesion and lens transparency
    Kulandaiappan Varadaraj; Fiscal Year: 2013
    ..The objectives will be pursued using structure-function approach and performing cytological, biochemical and molecular biological experiments as appropriate to verify the results. ..
  17. RPE Phenotype and Oxidative Stress
    Janice M Burke; Fiscal Year: 2013
    ..Antioxidants will also be tested to see if binding them to organelles helps the RPE sustain normal organelle motility despite ongoing photic stress associated with aging. ..
  18. POST TRANSCRIPTIONAL CONTROL OF GENE EXPRESSION IN THE LENS (LENS GENE EXPRESSION
    SALIL LACHKE; Fiscal Year: 2013
    ..Since mutation of one lens-specific RG component, TDRD7, causes human cataracts, these studies will also provide fundamental information about cataract formation. ..
  19. 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. ..
  20. Cataractogenesis, Connexin Mutants, and Genetic Modifiers
    Xiaohua Gong; Fiscal Year: 2013
    ..The information will be important for developing a new strategy to effectively prevent or delay nuclear cataracts, which account for about one-third of age-related cataracts. ..
  21. INTERCELLULAR COMMUNICATION IN THE LENS
    Lisa Ebihara; Fiscal Year: 2013
    ..abstract_text> ..