G protein-coupled receptors cool passion of 'kiss and run' nerve cells

A new subtlety in the process of how the body's nervous system relays information may hinge on how "wet" the "kiss" is when one neuron fires a packet of neurotransmitter across a synapse to a receptive nerve cell.

A team of neuroscientists led by University of Illinois at Chicago biology professor Simon Alford report the finding in the March 14 issue of the Proceedings of the National Academy of Sciences.

"Until recently, the neuroscience field was solidly behind the idea that these little packets, or vesicles, either released all or none of their neurotransmitter into the synaptic cleft," said Alford. "We've identified a specific molecular mechanism that targets the machinery that causes the fusion process and found that instead of an all-or-none release, the vesicle just kisses the cell's presynaptic membrane. Neuroscientists call it 'kiss and run.' When it does it, our lab has now shown that only a little bit of neurotransmitter is released.

"This is important for the cell because it implies that we can change the degree of information that's passed through the synapse every time it's fired," said Alford.

The process involves a receptor protein on a pre-synaptic nerve cell - the side that fires the packet of neurotransmitter - that is affected by 5-hydroxytryptamine, or 5-HT, a body chemical often associated with mood. When 5-HT binds to this cell receptor, it activates something called a G protein that is made of two subunits - one called alpha, the other beta-gamma. When these subunits are released, they activate the next step in a chain of events that move signal information through the nerve cell.

Alford's lab previously discovered that the beta-gamma subunit affects the molecular machinery that causes release of neurotransmitter - the amino acid glutamate.

"It's very fast," said Alford. "You turn on a G protein, and it immediately targets the mechanism to modify release."

On the receiving cell, the post-synaptic side, there is a range of protein receptors that vary in sensitivity to the amount of neurotransmitter that's released. Some scientists think if the release of neurotransmitter can be controlled to take into account the sensitivity and roles played by post-synaptic receptors, new drugs for treating a range of neurological conditions might be developed.

Alford thinks that controlling agent may turn out to be 5-HT.

"When you release 5-HT onto the terminal (pre-synaptic) cell, you can switch the relative activation of different receptors on the post-synaptic cell," he said. "You don't just change the amount of neurotransmitter released, but you change what's activated - the balance of different things that are activated in the next cell down the chain. In a sense, it's like you've turned a channel."

Heidi Hamm, professor and chair of pharmacology at Vanderbilt University, is a co-author of the PNAS paper. Other authors are Huzefa Photowala, Trillium Blackmer and Eric Schwartz, all former graduate students or post-doctoral researchers in Alford's UIC laboratory.