PETER YUEN'S HOME PAGE
 (under construction)

Research Interests:

Two lines of investigation in my laboratory are centered on soluble guanylyl 
cyclase:  1) understanding the mechanism of activation and 2) defining its 
roles ranging from the cell to the organism.  Like the particulate forms, 
soluble guanylyl cyclase is an intramolecular signal transduction unit, 
containing a receptor, transducer, and catalyst.  This enzyme is an 
alpha/beta heterodimer, with a prosthetic heme that serves as the receptor for 
nitric oxide.  Each subunit contains a putative catalytic domain homologous 
to particulate guanylyl cyclases and adenylyl cyclases.  Since both subunits 
are required for activity, it is possible that the catalytic site consists of two 
catalytic domains.  Alternately, each domain could represent a catalytic site 
that is kinetically indistinguishable from the other.  Because both subunits 
are sensitive to deletion mutagenesis, chimeras will be constructed to map 
domains responsible for catalysis and dimerization, and eventually heme 
binding and signal transduction.  The determinants for affinity and 
specificity of heterodimer formation will have a large impact on the ability to 
use dominant negative mutants to study function.

Our understanding of the function of cGMP as a signaling molecule has 
been limited, in part, by a lack of specific inhibitors of guanylyl cyclase.  
The two models mentioned above for the catalytic site led to the 
development of dominant negative mutants of the alpha subunit.  Both 
mutants (D to A substitutions in the putative catalytic domain) form 
heterodimers with wild-type beta subunit, but have no activity.  Stable 
overexpression of these mutants in cell lines abolishes the NO-stimulated 
cGMP response specifically.  Two additional methods are under 
development to broaden the scope of inhibition:  a) an adenovirus-based 
vector to infect primary cultured cells, and b) tissue-specific promoters that 
direct the expression in transgenic mice.  The latter approach may supercede 
current approaches toward inhibiting nitric oxide synthase as a means to 
develop disease models in the cardiovascular, immune, and central nervous 
systems.

 An alignment of guanylyl cylases


Selected Publications


1. Yuen, P.S.T., Potter, L.R., and Garbers, D.L. (1990)  A New Form of 
Guanylyl Cyclase is Preferentially Expressed in Rat Kidney.  Biochemistry  
29:10872-10878.        


2. Schulz, S., Green, C.K., Yuen, P.S.T., and Garbers, D.L. (1990)  
Guanylyl Cyclase is a Heat-Stable Enterotoxin Receptor.  Cell 63:941-948.        


3. Yuen, P.S.T. and Garbers, D.L. (1992)   Guanylyl Cyclase-linked 
Receptors.  Annu. Rev. Neurosci.  15:193-225.      


4. Yuen, P.S.T., Doolittle, L.K., and Garbers, D.L. (1994) Dominant 
Negative Mutants of Nitric Oxide-sensitive Guanylyl Cyclase. J. Biol. 
Chem. 269:791-793.       


5. Yuen, P.S.T., Takada, M., Thompson, D.K., and Garbers, D.L. (1994) 
Production  of Dominant Negative Mutations of Guanylyl Cyclase.    In 
Endothelium-Derived Factors and Vascular Functions.  Excerpta Medica 
International Congress Series 1051, pp. 205-210, T. Masaki, ed., Elsevier 
Science B.V., Amsterdam, The Netherlands, 1994.