Eric Beyer, PhD, MD

Professor, Department of Pediatrics
Section Chief, Pediatric Hematology/Oncology and Stem Cell Transplantation 

Committees on Cancer Biology,
Molecular Medicine, Cancer Research Center, and Chair, Committee on Cell Physiology

AB    Biological Sciences,
         University of Chicago

PhD   Physiology and Pharmacology,   
          University of California, San Diego

MD   University of California, San Diego

Research Summary

My laboratory is currently investigating the process of intercellular communication; our specific goal is a molecular understanding of the structure and function of gap junctions. Gap junctions are the specialized plasma membrane structures that contain low resistance channels linking adjacent cells. In excitable tissues, they permit electrical coupling; in non-excitable tissues, they permit passage of small molecules involved in metabolic support, growth control, and embryogenesis. They may also facilitate drug metabolite delivery between cells. 

We have cloned cDNAs corresponding to gap junction proteins from a number of different tissues and species.  These sequences demonstrate that there is a family of gap junction proteins (connexins) which are related in their transmembrane and extracellular regions, but which have unique cytoplasmic domains. Connexin-specific sequences confer different physiologic channel properties or regulation. We have also raised antibodies directed against specific domains within the connexin sequences. The cDNA and antibody regents are being used in a number of whole animal, tissue culture, and expression systems to investigate the structure and function of gap junctions and the regulation of intercellular communication. Our studies have demonstrated that different connexins have different expression patterns (eg. one isoform is specifically expressed in conducting tissue). We have found evidence of regulation of connexin proteins by phosphorylation and turnover/degradation.

 The transfection of communication-deficient cells with connexin sequences has demonstrated connexin-specific channel properties, permeabilities, and regulation. Site-directed mutagenesis is being used to identify sites within the connexins important in determining gating and permeability properties. We are also studying the sequences involved in oligomerization and cellular trafficking. 

Several aspects of these studies are of particular importance to cell physiology. We are using adenoviruses to express connexins in endothelial cells and other mature cell types to examine the roles of intercellular communication in these cells. We are using in situ hybridization to study the roles of connexins in embryonic development.

Some Selected Papers

Davis, L.M., Kanter, H.L., Beyer, E.C. and Saffitz, J.E. (1994).  Distinct gap junction phenotypes in cardiac tissues with disparate conduction properties.  J. Am. Coll. Cardiol., 24,1124-1132. 

Fick, J., Dazin, P., Westphale, E.M., Beyer, E.C. and Israel, M.A. (1995).  The extent of heterocellular communication is predictive of bystander cytotoxicity in vitro. Proc. Natl. Acad. Sci. U.S.A. 92, 11071-11075. 

 Laing, J.G. and Beyer, E.C. (1995). The gap junction protein connexin43 is degraded by the ubiquitin-proteasome pathway. J. Biol. Chem.270, 26399-26403. 

Veenstra, R.D., Wang, H-Z., Beblo, D.A., Chilton, MG., Harris, A.L., Beyer, E.C., Brink, P.R. (1995).  Selectivity of connexin-specific gap junction channels does not correlate with channel conductance. Circ. Res.77, 1156-1165. 

Larson, D.M., Wrobleski, M.J., Sagar, G.D.V., Westphale, E.M. and Beyer, E.C. (1997).  Connexin43 and connexin37 are differentially regulated in endothelial cells by cell density, growth, and TGF-B1. Am. J. Physiol. (Cell Physiol. 41)  272, C405-C415. 

Berthoud, V.M., Beyer, E.C., Kurata, W.E., Lau, A.F., Lampe, P.D. (1997). Connexin56 is phosphorylated within both the cytoplasmic loop and tail domains.     Eur. J. Biochem. 244, 89-97. 

Guerrero, P.A., Schuessler, R.B., Davis, L.M., Beyer, E.C., Johnson, C.M., Yamada K.A. and Saffitz, J.E. (1997).  Slow ventricular conduction in mice heterozygous for a connexin43 null mutation. J. Clin. Invest, 99, 1991-1998. 

Brink, P.R., Cronin, K., Banach, K., Peterson, E., Westphale, E.M., Seul, K.H., Ramanan, S.V. and Beyer, E.C. (1997).  Evidence for heteromeric gap junction channels formed by rat connexin43 and human connexin37. Am. J. Physiol. (Cell Physiol. 42) 273, C1386-C1396. 

Laing, J.G., Tadros, P.N., Westphale, E.M. and Beyer, E.C. (1997).  Degradation of connexin43 gap junctions involves both the proteasome and the lysosome. Exp. Cell Res. 236, 482-492. 

Seul, K-H., Tadros, P.N. and Beyer, E.C. (1997).  Mouse connexin40: gene structure and promoter analysis. Genomics 46, 120-126. 

Berthoud, V.M., Montegna, E.A., Paranjothi, N., Aithal, N.H., Brink, P.R. and Beyer, E.C. (2001).  Heteromeric connexons formed by the lens connexins, Cx43 and Cx56.  Eur. J. Cell Biol., 80, 11-19.

Pal, J.D., Berthoud, V.M., Beyer, E.C., Mackay, D., Shiels, A., Ebihara, L. (1999). Molecular mechanism underlying a Cx50-linked congenital cataract. Am. J. Physiol. (Cell Physiol.), 276, C1443-C1446.

Berthoud, V.M., Westphale, E.M., Grigoryeva, A. and Beyer, E.C. (2000). PKC isoenzymes in the chicken lens and TPA-induced effects on intercellular communication.  Invest. Ophthalmol. Vis. Sci., 41, 850-858.

Pal, J.D., Lui, X., Mackay, D., Shiels, A., Berthoud, V.M., Beyer, E.C. and Ebihara, L. (2000).  Connexin46 mutations linked to congenital cataract show loss of gap junction channel function.  Am. J. Physiol. (Cell Physiol.), 279, C596-C602.

Valiunas, V., Gemel, J., Brink, P.R. and Beyer, E.C. (2001).  Characterization of gap junction channels formed by co-expressed connexin40 and connexin43. Am. J. Phys. (Heart Circ.), 281, H1675-H1689.

Martinez, A., Moreno, A.P. and Beyer, E.C. (2002).  Connexin43 and Cx45 from heteromeric gap junction channels in which individual components determine permeability and regulation.  Circ. Res., 90, 1100-1107.

Valiunas, V., Beyer, E.C. and Brink, P.R. (2002).  Cardiac gap junction channels show quantitative differences in selectivity.  Circ. Res., 91, 104-111.

Updated 1/20/03.