Recent studies have shown that there are at least nine genes
coding for distinctive adenylate cyclases.
12 13 It has
been known for a number of years that the regulation of adenylate
cyclase activity is via stimulatory or inhibitory alpha subunits of G
proteins. Recently, it has been demonstrated that regulation by other
factors, especially Ca
2+, may be as
important.
14 Accumulating data show that most
cyclases, if not all, are multiply regulated, which may explain
many previously conflicting results. Specifically, it is now known that
besides the classically described regulation by
G
α subunits, protein kinase C,
Ca
2+, and βγ subunits of G proteins
all can regulate cyclase activity more effectively than
G
α subunits.
15 16 Interestingly,
stimulation of M1 and M3 receptors can lead to increased cAMP via
activation of the βγ subunits of cyclases II and IV (which are
stimulated by the βγ–G protein subunit and are
calmodulin-insensitive).
17 The cyclases and their
regulators can be classified into three groups as described by Cooper
et al.
14 : group 1, stimulated by calcium (AC-I, -III,
-VIII); group 2, nonstimulated by calcium (AC-II, -IV, -VII); and group
3, inhibited by calcium (AC-V, -VI). In situ hybridization has shown
that the individual cyclases have discrete distributions in the central
nervous system; certain isoforms are expressed uniquely in certain
areas of the brain.
18 19 20 21 22 23 This differential distribution
apparently serves to modulate differential signal transmissions. AC-II
is detected by Northern blot analysis in rat brain, olfactory
epithelium, olfactory bud, and lung but not in kidney, liver,
intestine, or heart.
23 AC-IV appears to be widely detected
by polymerase chain reaction analysis in rat brain, heart, intestine,
kidney, liver and lung, but not in testis.
24 In addition,
AC-II and AC-IV are both detected in increasing amounts by Northern
blot analysis in human and rat myometrium during
pregnancy.
25 Knowledge of the types and distribution of
adenylate cyclase isoforms present in the outflow apparatus will lend
insight into the ultimate mechanisms responsible for outflow facility
increases mediated by agents modulating cyclase activity. In the
present study, we characterized the presence and distribution of AC-II
and AC-IV in the human outflow pathway.