Miduturu Srinivas, PhD
SUNY College of Optometry
33 West 42nd Street New York, NY 10036


Research Description

 

Pharmacology of Lens and Neuronal Gap Junction Channels

The multigene family of proteins called connexins form intercellular gap junctions that directly mediate signaling between adjacent cells.  These cell–cell channels consist of two hemichannels or connexons from adjacent cells. In addition to forming gap junctions, some members of the connexin family can also function as transmembrane ion channels in the undocked state. Both cell-cell channels and hemichannels formed by connexins play a wide variety of roles in a number of different cell types and tissues, including the eye, and mutations in human connexins underlie a variety of disorders, including deafness, skin disease, demyelinating neuropathies and cataracts. 

One major goal of our laboratory is to determine the physiological roles of connexin channels in the eye, specifically the lens. Using electrophysiological recordings and cellular/molecular techniques, our studies with Dr Thomas White at SUNY Stony Brook indicate that factors that influence lens growth and transparency (e.g., growth factors and oxidative stress, respectively) have potent effects on connexin channel function. The potential ramifications for lens function and the mechanism by which they affect coupling is currently being pursued. A second major goal is to identify highly specific and selective inhibitors for connexin channels. Such inhibitors are likely to be useful for unraveling the physiological role of connexins and provide new and promising pharmacological targets in the treatment of several pathologies including epilepsy, cardiac arrhythmia and essential tremor. In collaboration with Dr. Heike Wulff at UC Davis, whose laboratory specializes in the design of small molecule ion channel modulators, we identified four new small molecule chemotypes that inhibit connexin channels in the low micromolar range. Structure-activity studies of these compounds are a current focus of interest. A third goal is to identify domains that are involved in gating of connexin channels by phosphorylation, pH and voltage. Using a combination of electrophysiological and molecular biology techniques, our collaborative studies with Vytas Verselis at AECOM indicate that amino acids in the first extracellular loop undergo significant rearrangements during channel closure by voltage and pH.

Educational Background

 

Pharmacy, Birla Institute of Technology and Science, BA, 1991

University of Florida, PhD Pharmacology, 1992-1997

Positions and Honors

 
  • 1991 Research Assistant, Department of Pharmacology, Central Drug Research Institute, Lucknow, India

  • 1992-1997 Graduate Assistant, Department of Pharmacology, University of Florida, Gainesville, FL

  • 1997-2001 Research Associate, Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY

  • 2001-2004 Instructor Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY

  • 2004 Assistant Professor, Department of Biological Sciences, SUNY College of Optometry, New York, NY

  • 1999 Grass Fellow, Marine Biology Laboratory, Woods Hole, MA

  • 2000 K. Hartline/S.W. Kuffler/F.R. Lillie Fellow, Marine Biology Laboratory, Woods Hole, MA

Publications

 

Belardinelli, L., Shryock, J.C., Song, Y., Wang, D., and Srinivas, M.: Ionic basis for the electrophyisological actions of adenosine in cardiomyocytes. FASEB J. 9:359-365, 1995.

Srinivas, M., Shryock, J.C., Scammells, J.C., Ruble, J., Baker, S.P., Belardinelli, L.: A novel irreversible antagonist of the A1-adenosine receptor. Mol. Pharmacol. 50:196-205, 1996.

Song, Y., Srinivas, M., Belardinelli, L.: Nonspecific inhibition of adenosine-activated K current by glybenclamide in guinea pig atrial myocytes. Am. J. Physiol. 271:H2430-H2437, 1996.

Srinivas, M., Shryock, J.C., Baker, S.P., Dennis, D.M., Belardinelli, L.: Differential A1-adenosine receptor reserve for two actions of adenosine in the guinea pig atria. Mol. Pharmacol. 52:683-691, 1997.

Srinivas, M, Rozental R., Kojima T., Dermeitzel R., Mehler M., Condorelli D. F., Kessler J. A., Spray D.C. Functional properties of channels formed by the neuronal gap junction protein connexin36. J Neurosci.19 (22):9848-55, 1999.

Srinivas, M., Costa M., Fort A., Fishman G.I., Spray D.C: Voltage dependence of macroscopic and unitary currents of gap junction channels formed by mouse connexin50 expressed in rat neuroblastoma cells. J Physiol (Lond).517 ( Pt 3):673-89, 1999.

Spray, D.C., Suadicani, S.O., Vink, M.J. and Srinivas, M. (2000) Gap junction channels and healing over of injury. In: Heart Physiology and Pathophysiology. N. Sperelakis, Y Kurachi, et al., eds., Academic Press, N.Y, pp. 149-174.

Rozental, R., Srinivas, M., Gokhan, S., Urban, M., Dermietzel, R., Kessler, J.A., Spray, D.C. and Mehler, M.F. (2000) Temporal expression of neuronal connexins during hippocampal ontogeny. Brain Res. Rev 32:57-71.

Hopperstad, M.G., Srinivas, M., and Spray, D.C. (2000) Properties of gap junction channels formed by Cx46/Cx50 gap junction channels. Biophys J. 79(4):1954-66.

Dermietzel R, Kremer M, Paputsoglu G, Stang A, Skerrett IM, Gomes D, Srinivas M, Janssen-Bienhold U, Weiler R, Nicholson BJ, Bruzzone R, Spray DC (2000). Molecular and functional diversity of neural connexins in the retina. J Neurosci. 20(22):8331-43.

Rozental, R., Srinivas, M., and Spray, D.C. (2001).How to close a gap junction channel: Efficacies and potencies of uncoupling agents. Methods Mol Biol.154: 447-76.

Srinivas, M., Hopperstad M.G., Spray DC (2001). Quinine blocks specific gap junction channel subtypes. Proc Natl Acad Sci. 98(19):10942-47.

De Pina-Benabou, M.H., Srinivas, M., Spray, D.C., and Scemes, E. (2001) CaM kinase pathway mediates the K+induced increase in gap junctional communication between mouse spinal cord astrocytes. J. Neurosci. Sept 1; 21(17):6635-43.

Spray, D.C., Suadicani, S.O., Srinivas, M., and Fishman, G.I.. (2002). Gap junctions in the cardiovascular system. In E.Page, H.A. Fozzard and R.J. Solaro (Eds.) Handbook of Physiology, Section 2: The Cardiovascular System, Vol I: The Heart, Oxford University Press Chapter 4, pp169-212.

Kojima, T., Srinivas, M., Fort, A., Urban, M., Lee, G-H., Sawada, N., and Spray, D.C. (2001) Growth-suppressive function of human connexin32 in a conditional immortalized mouse hepatocyte cell line. In Vitro Cell. Dev. Biol. 37:589-598.

Zoidl, G. Meier, C., Petrasch-Parwez, E., Zoidl, C., Habbes, H.-W., Kremer, M., Srinivas, M., Spray, D.C., and Dermietzel, R. (2002) Evidence for a role of the N-terminal domain of the neuronal connexin36 (Cx36) in subcellular localization. J Neurosci Research, 69 (4); 448-465.

White T. W., Srinivas M., Ripps H., Trovato-Salinaro A., Condorelli D. F., Bruzzone R. (2002) Virtual cloning, functional expression, and gating analysis of human connexin31.9. Am J Physiol Cell Physiol. 283(3):C960-70.

Spray, D.C., Rozental, R., Srinivas, M. (2002) Prospects for rational development of pharmacological gap junction channel blockers. Current Drug Targets 3(6):455-64.

Srinivas M., and Spray D.C. (2003). Closure of gap junction channels by arylaminobenzoates. Mol Pharmacol 63(6):1389-97.

Zoidl G, Bruzzone R, Weickert S, Kremer M, Zoidl C, Mitropoulou G, Srinivas M, Spray DC, Dermietzel R. (2004). Molecular cloning and functional expression of zfCx52.6: a novel connexin with hemichannel-forming properties expressed in horizontal cells of the zebrafish retina. J Biol Chem. 279(4):2913-21.

Srinivas M, Duffy HS, Delmar M, Spray DC. (2004) Pharmacological approaches to block gap junctions. In Cardiac Electrophysiology; From Bench to Bedside (Eds Zipes and Jalife).

Cruikshank S, Hopperstad M, Younger M, Connors B, Spray DC , Srinivas M (2004). Potent block of Cx36 and Cx50 gap junction Channels by mefloquine. Proc Natl Acad Sci U S A. 101(33):12364-9.

Srinivas M, Kronengold J, Bukauskas FF, Bargiello TA, Verselis VK. (2005) Correlative Studies of Gating in Cx46 and Cx50 Hemichannels and Gap Junction Channels. Biophys J. 88(3):1725-39

Nicchia GP, Srinivas M, Li W, Brosnan CF, Frigeri A, Spray DC. (2005) New possible roles for aquaporin-4 in astrocytes: cell cytoskeleton and functional relationship with connexin43. FASEB J. 19(12):1674-6.

Srinivas M, Calderon DP, Kronengold J, Verselis VK. (2006) Regulation of connexin hemichannels by monovalent cations. J Gen Physiol 127(1):67-75.

DeRosa AM, Mui R, Srinivas M, White TW (2006). Functional characterization of a naturally occurring Cx50 truncation. Invest Ophthalmol Vis Sci. 47(10):4474-81.

Bai D, Del Corsso C, Srinivas M, Spray DC (2006). Block of specific gap junction channel subtypes by 2-aminoethoxydiphenyl borate (2-APB). J Pharmacol Exp Ther. 319(3):1452-8

Martinez-Wittinghan FJ, Srinivas M, Sellitto C, White TW, Mathias RT. (2006) Mefloquine effects on the lens suggest cooperative gating of gap junction channels. J Membr Biol. 211(3):163-71.

Research Support During the Last Three Years

 

2002-2005:
Block of Lens and Neuronal Gap Junctions by Quinine, National Eye Institute, National Institutes of Health
RO1 (EY13869) (Miduturu Srinivas, P.I)
The goal of this project is to determine and characterize the block of gap junction channels by quinine and its derivatives.
Role: P.I.

2005-2009:
Block of Lens and Neuronal Gap Junctions by Quinine, National Eye Institute, National Institutes of Health
RO1 (EY13869) (Miduturu Srinivas, P.I)
The goal of this project is to use mefloquine to study the function of Cx50 in the lens.
Role: P.I.