SYDNEY: Researchers have found the trigger that activates sperm to start them swimming, which could lead to a male contraceptive and also explain the link between marijuana use and sperm damage.

Proteins called Hv1 in the tails, or flagella, of sperm eject protons in response to alkaline conditions outside the cell, such as in the vagina, said a study published today in the journal Cell. This elevates the pH inside the sperm and activates the flagella for swimming.

Biophysicist and study author Yuriy Kirichok, from the University of California in San Francisco, said scientists have searched for a link between sperm activation and alkalinity since the early 1980s. However, Hv1 was not discovered until 2006.

Possible male contraceptive

"What we're very excited about is that we've found the molecule that elevates sperm intracellular pH and we've found how that molecule is activated," he said.

Sperm are unable to achieve fertilisation until they go through the activation process, said Kirichok. They remain in this quiescent state inside the male reproductive tract to avoid burning out.

According to Kirichok, Hv1 is an attractive target for research into male fertility because there will be cheap, reproducible methods to search for a compound to control Hv1 and sperm activation.

Hv1 gives sperm a jump start

Hv1 is easily introduced into human embryonic kidney cells, which are favoured by drugs companies because they are easy to culture and test in the lab.

The inside of the male reproductive tract is slightly acidic, with a pH of less than 6.5. This prevents Hv1 from ejecting protons.

Proton ejection starts when the pH outside the cell becomes alkaline, such as in the female reproductive tract. The loss of protons raises the pH inside sperm cells to above 6.5 and this activates their flagella, so they can move around, said Kirichok.

Once the pH inside the cell reaches 7.0 (neutral) it activates an influx of calcium into the sperm flagellum to cause hyperactivation of sperm motility. At this moment, the beating of the flagella is sufficiently accelerated to give sperm the strength to tunnel into the female ovum.

Scientists have already established a link between marijuana use, sperm damage and impaired male fertility.

The study showed Hv1 is activated by the chemical endocannabinoid anandamide, which occurs naturally in the human body and acts in a similar way to the active chemicals found in marijuana.

Kirichok said this raises the possibility that marijuana activates sperm prematurely so they burn out before ejaculation.

"We can now hypothesise and try to explain the previous observations [of the link] that didn't have any molecular explanations," he said.

Tiny electrodes

To conduct the research, an electrode was attached to individual sperm using a delicate technique called 'patch clamping'. The electrical currents carried by protons across the cell wall were then measured under highly controlled acidity and voltage.

The response of the current of protons flowing from the cells closely matched the known behaviour of the protein HV1: it is relatively slow to activate and is inhibited by zinc, which is found in high concentrations in semen.

"This is an extremely abundant and the only sperm channel that can conduct protons," said Kirichok. "That's why we think at this moment that Hv1 is responsible for elevation of sperm intracellular pH and sperm activation in the female reproductive tract."

Absolutely exquisite

Biologist John Aitken from the University of Newcastle in Australia called the research "absolutely exquisite".

"I think it's a very beautiful and important piece of cell biology," he said.

However, Aitken noted that because Hv1 occurs in other parts of the body blocking it's function for the purpose of contraception could have side effects.

"Before we proceeded we would have to look at whether Hv1 is expressed in other parts of the body in order to make a judgement about how specific the effects would be on reproduction."

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