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Vol. 53, Issue 2, 182-187, February 1998
Department of Pharmacological and Physiological
Sciences, University of Chicago, Chicago, Illinois 60637
Forskolin potently activates all cloned mammalian adenylyl cyclases
except type IX by interacting with two homologous cytoplasmic domains
(C1 and C2) that form the catalytic core. A
mutational analysis of the IIC2 protein (C2
domain from type II adenylyl cyclase) and forskolin analogs suggests
that Ser942 interacts with the 7-acetyl group of forskolin. The
C1/C2 complex has only one forskolin, one ATP,
and one binding site for the 
subunit of the G protein that
stimulates adenylyl cyclase (Gs
) and its structure may
be modeled using the three-dimensional structure of
(IIC2/forskolin)2. The Ser942 mutation defines
which forskolin in the (IIC2/forskolin)2
structure exists in C1/C2 complex. Thus, the
forskolin-binding site is close to the Gs-binding site but distal (15-20Å) from the catalytic site. Mutation from Leu912 of
IIC2 protein to tyrosine or alanine severely reduces
Gs activation and completely prevents forskolin
activation. The corresponding residue of Leu912 is Tyr1082 at type IX
isoform of adenylyl cyclase. Similar to recombinant type IX enzyme,
soluble adenylyl cyclase derived from mouse-type IX adenylyl cyclase is
sensitive to Gs activation but not to forskolin.
Changing Tyr1082 to leucine makes soluble type IX adenylyl cyclase
forskolin-responsive.
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