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FRISC: The Faculty Research Interests Science Comparator |
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Professor of Pharmacology
Cell Regulation
Office: (214) 648-2370
FAX: (214) 648-8812
Cyclic AMP serves as an intracellular second messenger for a variety of
hormones and neurotransmitters that control the activity of adenylyl cyclase, the enzyme
responsible for synthesis of the nucleotide. Three types of membrane-associated proteins
are crucial for hormonal regulation of adenylyl cyclase activity: hormone receptors,
guanine nucleotide-binding regulatory proteins (G proteins), and adenylyl cyclase itself.
G proteins serve as essential coupling factors between receptors and adenylyl cyclase.
One, Gs, acts as an activator of cyclic AMP synthesis, while the other, Gi, is inhibitory.
G proteins are heterotrimers, consisting of alpha, beta, and gamma subunits. In the
basal state GDP is bound to alpha, and the protein is inactive. An activated hormone
receptor promotes dissociation of GDP from alpha and permits binding of GTP. Resultant
conformational changes cause dissociation of alpha-GTP from a complex of beta and gamma,
and both alpha-GTP and beta/gamma are thereby liberated to regulate the activities of
downstream effectors (such as adenylyl cyclase). The system is deactivated by hydrolysis
of GTP by alpha and subsequent association of alpha-GDP with beta/gamma. The rate of
deactivation of certain G protein alpha subunits is accelerated by members of a newly
appreciated family of so-called RGS proteins, which bind preferentially to the
transition-state complex of the G protein alpha subunit,
cDNA's that encode several different forms of adenylyl cyclase have been cloned and
expressed. These large proteins contain two alternating sets of membrane-spanning and
cytosolic domains. The different adenylyl cyclases have strikingly different patterns of
regulation by G protein alpha and beta/gamma subunits and by calmodulin. Large amounts of
the two cytosolic domains of adenylyl cyclase can be synthesized in bacteria. When mixed,
they display high levels of regulated enzymatic activity. This system has permitted
detailed study of mechanisms of regulation of adenylyl cyclase by G proteins, including
(with Stephen Sprang) solution of the crystal structure of a complex of Gs alpha with the
catalytic core of the enzyme.
Selected Publications:
Dessauer, C.W., Tesmer, J.J.G., Sprang, S.R., and Gilman, A.G. (1998) Identification of
a G i a binding site on type V adenylyl cyclase. J.
Biol. Chem. 273:25831.25839
Duncan, J.A. and Gilman, A.G. (1998) A cytoplasmic acylprotein thioesterase that
removes palmitate from G protein a subunits and p21 ras .
J. Biol. Chem 273:21752-21758
Berman, D.M. and Gilman, A.G. (1998) Mammalian RGS proteins: Barbarians at the
gate. J. Biol. Chem. 273:1269-1272
Tesmer, J.J.G., Sunahara, R.K., Gilman, A.G., and Sprang, S.R. (1997) Crystal structure
of the catalytic domains of adenylyl cyclase in a complex with G s a
-GTP g S. Science 278: 1907-1916
Page maintained by Stephanie
Robertson
Last updated: 17 Nov 2000
Extraction Method: Expand using Medical Synonyms-
Eliminated words list: MedlinePlus List
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Similarity Method: Weighted keyword count
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Database: Medline abstracts (1967 - Present)
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Score Calculation Method: Cosine Similarity Method
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Results computed on: 6/9/2006