Calcium regulation of the soluble adenylyl cyclase expressed in mammalian spermatozoa

In mammals, Ca2+ and HCO3- ions play a critical role in the regulation of sperm function, most likely by regulation of cAMP levels. Mammalian germ cells contain a soluble adenylyl cyclase (SAC) with properties distinct from the well characterized membrane-bound enzymes. Here we investigated whether the cyclase expressed in mature spermatozoa has the properties of SAC and whether it is regulated by Ca2+. In addition to an HCO3--dependent activation, the cyclase endogenous to human spermatozoa is stimulated 2- to 3-fold by Ca2+ in a concentration-dependent manner (EC50 approximate to 400 nM). In a similar fashion, Ca2+ activates the recombinant rat and human full-length SAC with similar EC50 values. The Ca2+ stimulation was also observed when SAC was activated with HCO3-, was independent of calmodulin, and was associated with an increase in v(max) without changes in K-m for ATP-Mg2+. An increase in intracellular Ca2+ by ionophore or by a muscarinic cholinergic receptor agonist increases cAMP in cells transfected with FL-hsAC, but not in mock-transfected cells. Similarly, both Ca2+ and HCO3- stimulate cAMP accumulation in human spermatozoa. These findings provide evidence that human spermatozoa express a cyclase with the properties of SAC and that Ca2+ can substitute for HCO3- in the stimulation of this enzyme, underscoring an important role for SAC in the control of sperm functions.