Abstract

The lens is an avascular organ and therefore relies on a unique microcirculatory system to transport nutrients and metabolites to its core. Gap junction channels are important components of this microcirculation and thus maintenance of homeostasis and transparency of the lens is critically dependent on their presence. Three gap junction proteins (connexins) are expressed in the lens. They are Cx43, Cx46 and Cx50. Mice lacking Cx50 or Cx46 develop nuclear cataracts. In addition, the lenses of Cx50 knockout mice are smaller than normal, implying an early developmental defect. We have developed an additional tool to discriminate between the different connexins. A potent and specific blocker of Cx50 gap junction channels was identified. This drug blocks Cx50 channels with an IC50 value of ~ 1 uM; block of the other two gap junctions expressed in the lens, Cx43 and Cx46, occurs only at 15- and 75-fold higher concentrations respectively. This observation forms the basis of this proposal. The overall goals of this project is to use a pharmacological approach to provide an understanding of the role of Cx50 gap junctions and hemichannels in maintaining transparency of the lens and in controlling lens growth. Such a pharmacological approach will also serve to complement studies on genetically engineered mice. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013869-05
Application #
7122353
Study Section
Special Emphasis Panel (ZRG1-AED (01))
Program Officer
Araj, Houmam H
Project Start
2002-02-01
Project End
2009-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
5
Fiscal Year
2006
Total Cost
$282,086
Indirect Cost

  Institution

Name
State College of Optometry
Department
Biology
Type
Schools of Optometry/Ophthalmol
DUNS #
152652764
City
New York
State
NY
Country
United States
Zip Code
10036

  Publications

Slavi, Nefeli; Wang, Zhen; Harvey, Lucas et al. (2016) Identification and Functional Assessment of Age-Dependent Truncations to Cx46 and Cx50 in the Human Lens. Invest Ophthalmol Vis Sci 57:5714-5722
Sanchez, Helmuth A; Slavi, Nefeli; Srinivas, Miduturu et al. (2016) Syndromic deafness mutations at Asn 14 differentially alter the open stability of Cx26 hemichannels. J Gen Physiol 148:25-42
Srinivas, Miduturu (2014) Delivery of glutathione to the lens nucleus. J Ophthalmic Vis Res 9:148-9
Rubinos, Clio; Villone, Krista; Mhaske, Pallavi V et al. (2014) Functional effects of Cx50 mutations associated with congenital cataracts. Am J Physiol Cell Physiol 306:C212-20
Sanchez, Helmuth A; Bienkowski, Rick; Slavi, Nefeli et al. (2014) Altered inhibition of Cx26 hemichannels by pH and Zn2+ in the A40V mutation associated with keratitis-ichthyosis-deafness syndrome. J Biol Chem 289:21519-32
Slavi, Nefeli; Rubinos, Clio; Li, Leping et al. (2014) Connexin 46 (cx46) gap junctions provide a pathway for the delivery of glutathione to the lens nucleus. J Biol Chem 289:32694-702
Sanchez, Helmuth A; Villone, Krista; Srinivas, Miduturu et al. (2013) The D50N mutation and syndromic deafness: altered Cx26 hemichannel properties caused by effects on the pore and intersubunit interactions. J Gen Physiol 142:3-22
Verselis, Vytas K; Srinivas, Miduturu (2013) Connexin channel modulators and their mechanisms of action. Neuropharmacology 75:517-24
Kronengold, Jack; Srinivas, Miduturu; Verselis, Vytas K (2012) The N-terminal half of the connexin protein contains the core elements of the pore and voltage gates. J Membr Biol 245:453-63
Rubinos, Clio; Sánchez, Helmuth A; Verselis, Vytas K et al. (2012) Mechanism of inhibition of connexin channels by the quinine derivative N-benzylquininium. J Gen Physiol 139:69-82

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