Professor of Biochemistry & Molecular Biology
PO Box 980614
Richmond, VA 23298-0614
Email: phratz@vcu.edu
Telephone: 804-828-3449
Education
- 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
Post-Doc
- 1983, McNeil Pharmaceutical Corporation, Spring House, PA. (Cardiovascular Pharmacology)
- 1987, University of Virginia, Charlottesville, VA. (Cardiovascular Physiology/Biochemistry)
Research
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.
Publications
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