General Scientific Background
cAMP is one of the most widely used signalling molecules in the animal kingdom, modulating numerous aspects of cell function from bacteria (e.g. nutritional sensing, motility) to higher eukaryotes (e.g. hormone responses, cell patterning, learning and memory).
In metazoans cAMP is synthesised by a seemingly ubiquitous family of plasma membrane spanning adenylyl cyclases (AC) (transmembrane adenylyl cyclase; tmAC) which mediate the responses of the cell to extracellular signals. Recently, a cytosolic form of AC (soluble adenylyl cyclase; sAC) has been identified in mammals and demonstrated to be molecularly and biochemically distinct from the tmACS. Therefore, although it remains to be uniquivocally proven, it appears that there are two distinct cAMP generating systems in mammalian cells; the tmACs that act at the plasma membrane and sAC that can act at distinct intracellular sites.
A number of modulators of tmAC activity have been identified e.g. heterotrimeric G proteins, Ca2+/Calmodulin, Protein Kinase A, and Protein Kinase C. In contrast, sAC is not stimulated by traditional activators of tmACs but is directly activated by bicarbonate ion in a pH independent manner. Although found predominantly in testis, sAC is expressed ubiquitously and HCO3– has many roles in eukaryotic physiology including pH homeostasis, cell volume control, gas exchange, reproductive function, and kidney function. A role for HCO3– in signal transduction through the synthesis of cAMP may have profound implications for our understanding of these systems.
The catalytic domains of sAC most closely resemble those of the cyanobacterial ACs rather than those of the tmACs and consistent with this a recombinant cyanobacterial AC, Spirulina platensis CyaC, was also demonstrated to be HCO3– responsive. Previous work on HCO3– responsive ACs in eukaryotes and cyanobacteria has focused on biochemical aspects establishing the principle that HCO3– has the capacity to function as a signal transduction molecule, but studies have yet to address the physiological relevance of this issue. The work in our laboratory is to establish the principle that HCO3– can act as a biologically relevant signalling molecule using the model cyanobacterium Synechocystis sp. PCC6803.
For a recent review of adenylyl cyclases in mammals try Patel et al., Gene (2001) 269, 13-25 and for a review dealing specifically with sAC try Wuttke et al., Journal of the Pancreas (2001) 2 (4 Suppl.), 154-8.