Eric Beyer, M.D., Ph.D.
Studies of Gap Junction-Mediated Intercellular
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 which 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. In migratory cells (such as macrophages), which also express these proteins, they may facilitate more transient interactions. Recently, we and others have shown that connexins can make “hemi-channels” that link the cytoplasm and extracellular space; opening of connexin hemichannles may have major physiological and pathophysiological conasequences.
My laboratory has made a number of major contributions to this field starting with the cloning of cDNAs corresponding to gap junction proteins from a number of different tissues and species. These sequences demonstrated 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. Expression of these cloned connexins demonstrated that c onnexin-specific sequences confer different physiologic channel properties and regulation. We have also extensively studied the cellular biology of gap junction assembly and degradation. We have found evidence of regulation of connexin proteins by post translational modifications (including phosphorylation and ubiquitinylation).
Ongoing studies are focused in multiple areas:
· Relationships between connexin sequence/structure and channel function
· Cellular biology of gap junctions
· The role of gap junction channels in cancer biology and treatment
· Contributions of connexins to normal cardiac conduction and arrhythmias
· Roles of connexin mutations in the pathogenesis of cataracts
· Connexin hemichannels and cell injury
Veenstra RD, Wang HZ, Westphale EM, Beyer EC: Multiple connexins confer distinct regulatory and conductance properties of gap junctions in developing heart. Circ Res 1992; 71:1277-1283.
Reed KE, Westphale EM, Larson DM, Wang HZ, Veenstra RD, Beyer EC: Molecular cloning and functional expression of human connexin37, an endothelial cell gap junction protein. J Clin Invest 1993; 91:997-1004.
Fick J, Dazin P, Westphale EM, Beyer EC, Israel MA. The extent of heterocellular communication is predictive of bystander cytotoxicity in vitro. Proc. Natl. Acad. Sci. U.S.A. 1995; 92: 11071-11075.
Laing JG, Beyer EC. The gap junction protein connexin43 is degraded by the ubiquitin-proteasome pathway. J. Biol. Chem. 1995; 270: 26399-26403.
Martinez A, Moreno AP, Beyer EC: Connexin43 and Cx45 form heteromeric gap junction channels in which individual components determine permeability and regulation. Circ. Res. 2002; 90:1100-1107.
Berthoud VM, Singh R. Minogue PJ, Ragsdale CW, Beyer EC. Highly restricted pattern of connexin36 expression in chick embryo somites. Anat. Embryol. 2004 209:11-18.
Gemel,J., Lin,X., Veenstra,R.D., and Beyer,E.C. N-terminal residues in Cx43 and Cx40 determine physiological properties of gap junction channels, but do not influence heteromeric assembly with each other or with Cx26. J. Cell Sci. 2006; 119, 2258-2268.
Chung J, Berthoud VM, Novak L, Zoltowski R, Heilbrunn B, Minogue PJ, Liu X, Ebihara L, Kuszak J, Beyer EC. Transgenic overexpression of connexin50 induces cataracts. Exp.EyeRes. 2007 84(3):513-28.
Wang M, Berthoud VM, Beyer EC. Connexin43 increases the sensitivity of prostate cancer cells to TNFα induced apoptosis. J.Cell Sci. 2007 120:320-329.
Kyle JW, Minogue PJ, Thomas B, Lopez-Domowicz D, Berthoud VM, Hanck DA, Beyer EC. An intact connexin N-terminus is required for function, but not for gap junction formation. J.Cell Sci. 2008; 121:2744-50.
Kyle JW, Berthoud VM, Kurutz J, Minogue PJ, Greenspan M, Hanck DA, Beyer EC. The N-terminus of connexin37 contains an α-helix that is required for function. J.Biol.Chem. 2009;284:20418-27.
Minogue PJ, Tong J-J, Arora A, Russel-Eggitt I, Hunt DM, Moore AT, Ebihara L, Beyer EC, Berthoud VM. A mutant Connexin50 with enhanced hemichannel function causes cell death. Invest.Ophthalmol.Vis.Sci. 2009 50:5837-5845.
Lichtenstein A, Minogue PJ, Beyer EC, Berthoud VM. Autophagy: A pathway that contributes to connexin degradation. J. Cell Sci. (in press)