Cyclic AMP serves as an intracellular "second messenger" for a variety of hormones and neurotransmitters that control the activity of adenylyl cyclases, the enzymes responsible for synthesis of the nucleotide. Three types of membrane-associated proteins are essential for hormonal regulation of adenylyl cyclase activity: hormone receptors, guanine nucleotide-binding regulatory proteins (G proteins), and the adenylyl cyclases themseleves. G proteins serve as essential coupling factors between receptors and adenylyl cyclases. 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 at least partial 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 cyclases). 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 family of so-called RGS proteins, which bind preferentially to the transition-state complex of the G protein alpha subunit.
Multiple forms of adenylyl cyclase synthesize cyclic AMP. 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.
RESEARCH INTERESTS
G Proteins
Adenylyl Cyclases
RGS Proteins
Cellular Signaling
SIGNIFICANT PUBLICATIONS
Ross, E.M., Howlett, A.C., Ferguson, K.M., and Gilman, A.G., "Reconstitution of hormone-sensitive adenylate cyclase activity with resolved components of the enzyme." J. Biol. Chem., 253:6401-6412, 1978
Bokoch, G.M., Katada, T., Northup, J.K., Ui, M., and Gilman, A.G., "Purification and properties of the inhibitory guanine nucleotide-binding regulatory component of adenylate cyclase" J. Biol. Chem., 259:3560-3567 See also pp. 3568-3395., 1984
Krupinski, J., Coussen, F., Bakalyar, H. A., Tang, W.-J., Feinstein, P. G., Orth, K., Slaughter, C., Reed, R. R., and Gilman, A. G., "Adenylyl cyclase amino acid sequence: possible channel- or transporter-like structure." Science, 244:1558-1564, 1989
Taussig, R., Iniguez-Lluhi, J. A., and Gilman, A. G., "Inhibition of adenylyl cyclase by Gi∀" Science, 261:218-221, 1993
Tesmer, J.J.G., Sunahara, R.K., Gilman, A.G., and Sprang, S.R., "Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gs∀AGTP(S." Science, 278:1907-1916, 1997
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