Michael D. Chinkers, Ph.D.
||Vanderbilt University, Nashville, TN
||State University of New York at Stony Brook
Our research revolves around signaling pathways initiated by receptors for the natriuretic peptides, ANP, BNP, and CNP. These transmembrane receptors were shown 20 years ago to be guanylyl cyclases that are activated upon ligand binding, producing the second messenger, cyclic GMP. One of the most important biological roles of these receptor/guanylyl cyclases is to lower blood pressure by relaxing blood vessels and by increasing their permeability. The regulation of natriuretic peptide receptors by phosphorylation led us to characterize a protein phosphatase, PP5, that bound to the ANP receptor. The association of PP5 with heat shock protein 90 and other TPR proteins that regulate protein folding has been a focus of our lab for a number of years, with projects studying the role of these proteins in both natriuretic peptide and steroid signaling.
More recently, we have found evidence in the pulmonary vasculature for differential localization of both the natriuretic peptide receptor/guanylyl cyclases that produce cyclic GMP and the cyclic nucleotide phosphodiesterases that hydrolyze cyclic GMP. In different pulmonary vascular beds, ANP and CNP receptors are present at different levels, are found in different areas of the plasma membrane, and are associated with different phosphodiesterases. Our current research focuses on the molecular basis for these observations. Given the importance of natriuretic peptides and of cyclic GMP in regulating vascular function, and given the pharmacological importance of this pathway in treating pulmonary hypertension, we are hopeful that obtaining a better understanding of how guanylyl cyclase activity is regulated differently in different pulmonary blood vessels may eventually help in developing better treatments for pulmonary disease.
- Chinkers, M., Garbers, D.L., Chang, M.-S., Lowe, D.G., Chin, H., Goeddel, D.V., and Schulz, S. (1989) A membrane form of guanylate cyclase is an atrial natriuretic peptide receptor. Nature 338, 78-83.
- Chinkers, M. (1994) Targeting of a distinctive protein serine phosphatase to the protein kinase-like domain of the atrial natriuretic peptide receptor. Proc. Natl. Acad. Sci. U. S. A. 91, 11075-11079.
- Chen, M.-S., Silverstein, A.M., Pratt, W.B., and Chinkers, M. (1996) The tetratricopeptide repeat domain of protein phosphatase 5 mediates binding to glucocorticoid receptor heterocomplexes and acts as a dominant negative mutant. J. Biol. Chem. 271, 32315-32320.
- Russell, L. C., Whitt, S. R., Chen, M.-S., and Chinkers, M. (1999) Identification of conserved residues required for the binding of a tetratricopeptide repeat domain to heat shock protein 90. J. Biol. Chem. 274, 20060-20063.
- Wu, S., Moore, T. M., Brough, G. H., Whitt, S. R., Chinkers, M., Li, M., and Stevens, T. (2000). Cyclic nucleotide gated channels mediate membrane depolarization following activation of store operated calcium entry in endothelial cells. J. Biol. Chem. 275, 18887-18896.
- Chinkers, M. (2001) Guanylate cyclases. In Encyclopedia of Molecular Medicine (T. E. Creighton, ed.) John Wiley and Sons, Inc., New York, N.Y., pp. 1531-1533.
- Kumar, R., Grammatikakis, N., and Chinkers, M. (2001) Regulation of the atrial natriuretic peptide receptor by heat shock protein 90 complexes. J. Biol. Chem. 276, 11371-11375.
- Ramsey, A.J., and Chinkers, M. (2002) Identification of potential physiological activators of protein phosphatase 5. Biochemistry 41, 5625-5632.
- Chinkers, M. (2004) PP5: The TPR phosphatase. Topics in Current Genetics 5, 107-130.
- Gerges, N. Z., Tran, I. C., Backos, D. S., Harrell, J. M., Chinkers, M., Pratt, W. B., and Esteban, J. A. (2004) Independent functions of hsp90 in neurotransmitter release and in the continuous synaptic cycling of AMPA receptors. J. Neurosci. 24, 4758-4766.
- Carrigan,, P.E., Riggs, D.L., Chinkers, M., and Smith, D.F. (2005) Functional comparison of human and Drosophila Hop reveals novel role in steroid receptor maturation. J. Biol. Chem. 280, 8906 - 8911.
- Conde, R., Xavier, J., McLoughlin, C., Chinkers, M., and Ovsenek, N. (2005) Protein phosphatase 5 is a negative modulator of heat shock factor 1. J. Biol. Chem. 280, 28989-28996.
- Ramsey, A. J., Russell, L. C. and Chinkers, M. (2009) C-terminal sequences of hsp70 and hsp90 as non-specific anchors for TPR proteins.Biochem. J. 423, 411-419.