Mechanisms controlling intercellular signaling via gap junctions
in the cardiovascular system; role of gap junctions in growth control,
response to injury, cardiac arrhythmias and vascular disease.
Gap junction channels provide a conduit for the diffusion of
small molecules between neighboring cells. By providing a pathway
for electrical communication, gap junctions make coordinated contractile
activity of the heart and blood vessels possible. Aberrant gap
junction function leads to cardiac arrhythmias and spasm of blood
vessels. Gap junctions are also believed to support normal growth,
development, and differentiation of cells, and may be critical
to long-term tissue remodeling (e.g. in response to tissue injury).
These latter functions may reflect the capacity of gap junctions
to mediate intercellular exchange of signaling molecules and metabolites.
Research in my lab is focused on understanding the function of gap junctions, especially those common to the cells of the cardiovascular system. Channel number, open probability and permeability determine gap junction function. These determinants of function are regulated acutely by signaling cascades and over a longer time frame through gene expression of the same or different gap junction proteins (connexins). We are investigating when, how and why cells of the cardiovascular system regulate the level of intercellular coupling in the course of development, disease or injury, and in response to common therapeutic agents.
We demonstrated using electrophysiologic and molecular approaches that co-expressed Connexin (Cx) 40 and Cx43 form mixed (heteromeric) channels. These mixed channels are closed more readily than non-mixed channels by volatile anesthetics and recent studies indicate that their permeability is related to the ratio of expressed connexins. We are currently 1) exploring the functional consequences of such long-term changes in connexin expression on growth factor-induced acute regulation of gap junction function, and 2) evaluating whether such long-term changes in expression are necessary to normal growth and response to injury in the vasculature. Findings from these experiments will provide novel insights into cardiovascular functionin health and disease.
Cottrell, G.T., Y. Wu, J.M. Burt. Cx40 and Cx43 expression ratio
influences heteromeric/heterotypic gap junction channel properties.
Am. J. Physiology: Cell Physiol. 282: C1469-C1482, 2002.
Cottrell, G.T. and J.M. Burt. Heterotypic gap junction channel
formation between heteromeric and homomeric Cx40 and Cx43 connexons.
Am. J. Physiol.: Cell Physiology 281:C1559-C1567, 2001.
Burt, J.M., A.M. Fletcher, T.D. Steele, Y. Wu, G.T. Cottrell,
D.T. Kurjiaka: Alteration of Cx43:Cx40 expression ratio
in A7r5 cells. Am. J. Physiology: Cell Physiology, 280:C500-C508,
2001.
Lampe, P.D., E.M. TenBroek, J.M. Burt, W.E. Kurata, R.G. Johnson
and A.F. Lau: Phosphorylation of connexin43 on serine368 by protein
kinase c regulates gap junctional communication. J. Cell Biol.,
149:1503-1512, 2000.
He, D.S. and J. M. Burt: Mechanism and selectivity of halothane’s
effects on gap junction channel function. Circ. Res., 86:e104-e109,
2000.
He, D.S., J.X. Jiang, S.M. Taffet and J.M. Burt: Formation
of heteromeric gap junction channels by connexins 40 and 43 in
vascular smooth muscle cells. Proc. Natl. Acad. Sci., 96:6495-6500
1999.
Kurjiaka, D.T., T.D. Steele, M.V. Olsen and J.M. Burt: Gap junction
permeability is diminished in proliferating vascular smooth muscle
cells. Am. J. Physiology, Cell Physiology, 275:C1674-C1682, 1998.
Warn-Cramer, B.J., G.T. Cottrell, J.M. Burt and A.F. Lau:
Regulation of connexin43 gap junctional intercellular communication
by mitogen-activated protein kinase. J. Biol. Chem., 273(15):9188-9196,
1998.
