Paul H. Ratz, Ph.D.Professor of Biochemistry & Molecular Biology
PO Box 980614
Richmond, VA 23298-0614
- B.S., 1977, Pennsylvania State University, State College, PA (Biology)
- Ph.D., 1982, Hershey Medical Center of the Pennsylvania State University, Hershey, PA. (Physiology) State
- 1983, McNeil Pharmaceutical Corporation, Spring House, PA. (Cardiovascular Pharmacology)
- 1987, University of Virginia, Charlottesville, VA. (Cardiovascular Physiology/Biochemistry)
Smooth muscle is the cell motor responsible for contraction of the vasculature, bladder, bronchioles and gut. As such, smooth muscle contraction plays a role in several disorders, such as hypertension, vasospasm, overactive bladder leading to incontinence, and asthma. The overall goal of my laboratory is to identify cell mechanisms regulating smooth muscle contraction. This may permit the identification of unique drugs to selectively alter contractility of one smooth muscle type without greatly affecting other smooth muscle types, and the cell signaling of other cell types.
Smooth muscle contraction: Smooth muscles use multiple mechanisms to regulate contraction and relaxation. A primary mechanism operates through thick filaments via Ca2+-activated myosin light chain (MLC) kinase (MLCK), causing increased MLC phosphorylation and contraction. Additional mechanisms include 1) modulation of MLCK, 2) phosphorylation of MLCs by other kinases, such as rhoA kinase (ROK), ZIP-like kinase (ZIPLK), integrin-linked kinase (ILK), MAPKAP-2, and p21-kinase (PAK), 3) inhibition of MLC phosphatase by ROK and PKC, and 4) regulation of thin filaments by caldesmon and calponin. Cyclic nucleotide-dependent protein kinases (PKA and PKG) can negatively modulate some of these systems, leading to relaxation. The precise mechanisms used by different smooth muscle types remain to be determined. We have found that bladder wall (detrusor) smooth muscle appears to be less dependent on MLCK than vascular muscle, and more dependent on other kinases, such as ROK and possibly ZIPLK. We are investigating length-dependent regulation of detrusor contractile mechanisms.
Ca2+ sensitization: This term is used to describe any mechanism that potentiates Ca2+-dependent (i.e., MLCK-dependent) activation of contraction. Receptor stimulation by contractile agonists, such as norepinephrine or acetylcholine, causes Ca2+ sensitization via ROK- and PKC-induced inhibition of MLC phosphatase (MLCP). My laboratory provides data indicating that 1) K+-depolarization increases Ca2+ sensitization (i.e., receptor stimulation is not necessary to cause Ca2+ sensitization) by causing a Ca2+-dependent translocation of ROK to caveolae, signalosomes at the cell membrane, and 2) the history of receptor stimulation directly modulates the degree of Ca2+ sensitization produced by any stimulus capable of increasing Ca2+ sensitivity. This history-dependence is a form of cell information storage, or memory. We are investigating the mechanisms regulating smooth muscle memory of receptor activation in large and small arteries.