For sperm to find their way to the egg after ejaculation, a wide arsenal of molecular signals is required. One such signal is a small cellular messenger substance, called cAMP, which plays a central role in this process. Without it, sperm literally fall by the wayside.
cAMP causes the tail of the sperm to beat rhythmically, similar to the kicking of legs when swimming, thus propelling them forward. However, the tail serves not only as a motor, but also as a rudder that controls the direction of swimming. Sperm find their way to the egg via attractants, which they “sense” with the help of special sensors, known as receptors, on their tails. Without cAMP, sperm cannot move, leading to infertility in humans and animals.
Universal or specific?
In sperm, cAMP is produced by an enzyme called soluble adenylyl cyclase (sAC). In mammals, including humans, sAC is activated by high concentrations of bicarbonate (HCO3-) in the semen and fallopian tubes. It was assumed that this mechanism is universal in the animal kingdom, from corals to humans. However, enzyme activation by bicarbonate may be more specific to mammals, as researchers led by Benjamin Kaupp and Olivia Kendall have now discovered in studies on sea urchins and fish.
pH value as regulator
Sea urchins are spiny marine animals that inhabit the seafloor. They reproduce sexually by releasing sperm and eggs into the open water in a process known as mass spawning. “In sea urchin sperm and generally in marine organisms with external fertilization, such as fish, sAC regulation by bicarbonate is therefore hardly plausible as the concentration in seawater is up to ten times lower than in mammalian sperm,” explains Kaupp, who is an emeritus director at the Max Planck Institute (MPI) for Multidisciplinary Sciences and a senior professor at the University of Bonn. “The question for us was: If bicarbonate does not regulate sAC and trigger the increase in cAMP concentration, what else does?”
As Kaupp and Kendall discovered in collaboration with researchers at the Center of Reproductive Medicine and Andrology at the University of Münster, the Technical University of Berlin, and the MPI for Neurobiology of Behavior in Bonn, sAC in sea urchin sperm is a pH sensor: The enzyme is directly controlled by the pH value.
Fitter sperm due to higher pH value
“Sperm are completely immotile in testis. They become motile after ejaculation. First, the pH value rises and the sperm interior becomes more alkaline. This activates sAC and increases the cAMP concentration. Attractants that guide sperm to the egg then trigger a second rise in pH. This leads to further activation of sAC and another increase in cAMP concentration,” reports Olivia Kendall, a doctoral student at the University of Bonn and first author of the paper now published in the journal PNAS.
cAMP fulfills two central tasks
The new findings by Kaupp’s team underscore and clarify the importance of the messenger cAMP in sperm. In previous studies, the group had already demonstrated that cAMP activates pacemaker ion channels in sea urchin sperm. These channels are widespread in evolution and are found in many tissues. In the heart, for instance, they control rhythmic electrical excitation. Pacemaker ion channels also “time” the rhythmic swimming motion of sperm. This is regulated by the rise and fall in the concentration of attractants that guide the sperm towards the egg. This directed movement in response to chemical substances is called chemotaxis. “In a nutshell, our current and previous results show that cAMP fulfills two central tasks: It both initiates motility and plays an important role in the chemotactic signaling pathway,” Kaupp explains.
sAC as pH sensor in fish
sAC’s function as a pH sensor is not limited to sea urchins, as the researchers demonstrated in experiments with fish. In salmon sperm, a higher pH value also causes the cAMP level to rise. The team also demonstrated that sAC from sea urchins and salmon lacks two crucial amino acids found in the mammalian enzyme that mediate the response to bicarbonate. These results suggest that pH regulation is widespread in marine invertebrates and fish.
But why are there two such fundamentally different regulatory mechanisms in nature? The key is the low bicarbonate content in water. “The regulation of sAC by pH or hydrogen carbonate represents an adaptation to environments with either low or high hydrogen carbonate content,” says Kai Korsching, a former PhD student in Kaupp’s team and now a researcher at the University of Münster.
Reproduction at risk?
The new findings of the study are also relevant in view of the climate crisis. Because sAC in marine organisms is controlled by pH, climate change could harm them. “The fact that lakes and oceans are acidifying as a result of climate change and rising carbon dioxide levels in the air may affect the reproductive success of these species,” says Kendall.