The second messenger molecule cAMP, which modulates cell growth and differentiation in organisms from bacteria to higher eukaryotes, is produced by adenylyl cyclases. Mammals possess two distinct classes of adenylyl cyclase, the hormone-responsive, transmembrane adenylyl cyclases (tmAC) and the bicarbonate-regulated Soluble Adenylyl Cyclase (sAC). In collaboration with Dr. Jochen Buck, Dr. Levin was the first to purify and clone mammalian sAC and demonstrate its regulation by bicarbonate ions. Because bicarbonate is in nearly instantaneous equilibrium with carbon dioxide and intracellular pH due to the ubiquitous presence of carbonic anhydrases, sAC is poised to respond to changes in carbon dioxide production and intracellular pH and thereby sense the metabolic state of the cell.
In eukaryotic cells, second messengers, such as cAMP, can play multiple, disparate roles within in a single cell. This is achieved by compartmentalization into independently regulated signaling microdomains distributed throughout the cell. For example, in a single cell, sAC-generated cAMP modulates distinct effectors from tmAC-generated cAMP. We have shown sAC is distributed to intracellular sites containing cAMP effectors; therefore, it seems to represent the source of second messenger for intracellular cAMP signaling microdomains.
