Jeff Walker

Professor
Ph.D., 1982, University of California, Davis

Contact Information
Email: jwalker@physiology.wisc.edu
(608) 262-6941 Phone
(608) 265-5512 Fax

Research Interests
Signal transduction in the cardiovascular system

Visit the Walker Lab

The long term objective of the research program is to identify cellular and molecular mechanisms that regulate heart muscle contraction. Force producing cells in the heart (myocytes) respond to a variety of extracellular stimuli including hormones, neurotransmitters, growth factors, mechanical stress and low oxygen.

Receptors for many of these stimuli are coupled to the phosphoinositide/diacylglycerol/protein kinase C signaling system, and our challenge is to elucidate the molecular details of how this pathway functions to regulate contractility, cardioprotection, gene expression and growth.

Signaling mechanisms involving protein kinase C are also likely to have important implications in the etiology and treatment of cardiac hypertrophy, heart failure and other disease conditions (e.g. diabetes) where cardiac function is impaired.

Several complimentary approaches are being used to study protein kinase C mediated regulation of contractility in the mammalian heart. Mechanical, electrophysiological, and confocal fluorescence measurements on isolated cardiac myocytes are performed to evaluate the involvement of protein kinase C in pathways activated by surface receptors for noradrenaline, endothelin and adenosine, or by intracellular messengers such as inositol phosphates, calcium, diacylglycerol and arachidonic acid.

A leading hypothesis generated by our work is that separate isoforms of protein kinase C, epsilon and delta, respond to different intracellular signals and carry out distinct but complimentary cellular functions.

Protein kinase C-epsilon anchors at key sites on the sarcomere and enhances myocyte function in the short term by phosphorylating specific calcium channels and contractile proteins. Protein kinase C-delta translocates to the nucleus where it regulates gene expression for longer term changes in myocyte physiology.

These hypotheses are being tested by biophysical, imaging and molecular approaches with an emphasis on identifying and manipulating organelle-specific anchoring proteins, and creating mutations in critical phosphorylation sites in cultured myocytes and in mouse hearts.

The laboratory is also actively involved in the development of optical probes so that signaling mechanisms can be dissected with high temporal and spatial resolution using modern light microscopy. Bioactive probes currently under development include membrane permeases capable of carrying peptide/protein cargo across biological membranes, peptide activators and inhibitors of protein kinase C, toxins targeted against calcium channels, and light activated forms of various second messengers.

Selected Publications

• Walker, J.W. (1999) Kinetics of the actin-myosin interaction. In: Handbook of Physiology, The Cardiovascular System. Eds. R.J. Solaro, H. Fozzard. Oxford University Press, NY. in press.
   
• Huang, X.P., Pi, Y.Q., Lee, K.J., Henkel, A.S., Gregg, R.G., Powers, P.A. and Walker, J.W. (1999) Cardiac troponin I gene knockout: A mouse model of myocardial troponin I deficiency. Circulation Research. 84:1-8.
  Abstract | Full Text | PDF
   
• Pi, Y.Q. and Walker, J.W. (1998) Role of intracellular calcium and pH in the positive inotropic response of cardiomyocytes to diacylglycerol. American Journal of Physiology. 275:H1473-H1481.
  Abstract | Full Text | PDF
   
• Walker, J.W., Gilbert, S.H., Drummond, R.M., Yamada, M., Sreekumar, R., Carraway, R., Ikebe, M. and Fay, F.S. (1998) Signaling pathways underlying Eosinophil motility revealed using caged peptides. Proc. Natl. Acad. Sci USA, 95:1568-1573.
  Abstract | Full Text | PDF
   
• Sreekumar, R., Ikebe, M., Fay, F.S. and Walker, J.W. (1998) Biologically active peptides caged on tyrosine. Methods in Enzymology, 291:78-94.
• Huang, X.P., Pi, Y.Q., Lokuta, A.J., Greaser, M.L. and Walker, J.W. (1997). Arachidonic acid stimulates protein kinase C-epsilon redistribution in heart cells. J. Cell Sci. 110:1625-1634.
  Abstract | PDF
   
• Pi, Y.Q., Sreekumar, R., Huang, X.P. and Walker, J.W. (1997). Positive inotropy mediated by diacylglycerol in rat ventricular myocytes. Circ. Res. 81:92-100.
  Abstract | Full Text | PDF

top