07 April 2011

Neurotransmitter release without calcium

ResearchBlogging.orgWhen I was in graduate school, my boss went to an IBRO conference that contained a point / counterpoint pair of talks about what triggered the release of chemicals from one neuron that could be picked up by another. One researcher argued that calcium rushing into the neurons was the sole cause of the neurotransmitter release. The other argued that there wasn’t enough evidence to say definitively that calcium was both necessary and sufficient for neurotransmitter release.

A new paper may make both speakers wrong. Shakiryanova and colleagues claim to have found neurons that release neurotransmitter without calcium being involved at all.

My initial thought when I read the title of this paper was, “How silly of me to think that every neuron would have to use calcium to trigger neurotransmitter release. We see so much variation in neurons. Some neurons use calcium instead of sodium for spikes, and some neurons don’t spike at all. Why couldn’t there be a case of some neurons using something besides calcium?”

How do you prove the neurons don’t use calcium? And what do they do instead of calcium?

The basic experiment is very simple. Record from a presynaptic neuron, and target cell – a muscle in this case – and take out the calcium. If the target cell can still do anything in response, there’s your proof, more or less.

Now, the details are much more complicated. Because this is in a fruit fly maggot, they’re using genetically modified flies that have a neuroactive chemical that glows under the right light.

There were two different chemicals that could trigger the neurotransmitter release. One is called forskolin. It activates adenylyl cyclase, which in turn activates cyclic adenosine monophospate (also known as cyclic AMP), and that causes neuroactive chemical release.

The other chemical is something I’m more familiar with: octopamine, which has received a lot of attention for its role in regulating behaviour in invertebrates. For maximum effect, octopamine makes the neuron release calcium stored inside it, and that triggers neurotransmitter release, so calcium hasn’t been completely cut out of the system.

Many of the experiments are... complicated... for anyone who isn’t familiar with Drosophila mutations and cyclic AMP chemistry. This is indirect way of me saying that I struggled to make sense of this paper. This paper is acrotastic, swimming in abbreviations and symbols.

I am left with many questions. It’s not clear to me what the source of either forskalin or octopamine might be in this system. The authors seem to be suggesting that these chemicals are causing a sort of slow, gradual release of neurotransmitter. Some non-spiking neurons release some neurotransmitter tonically, so perhaps this system is a little like those.

If I understand right, calcium is still the only way known to trigger neurotransmitter release from an action potential. But I can’t help but think that it’s just a matter of time before someone finds a neuron where the spike triggers some other ion to rush in and cause neurotransmitter release.

Tangent: The authors call octopamine a “homolog” to norepinephrine. In evolution, “homolog” means “related by common ancestry,” which doesn’t apply to molecules. In molecular biology, “homolog” often means “similar sequences of DNA,” or some other long polymer, which also doesn’t apply here. Anyone familiar with some other meaning of the word I’m no familiar with?

Reference

Shakiryanova D, Zettel G, Gu T, Hewes R, Levitan E. 2011. Synaptic neuropeptide release induced by octopamine without Ca2+ entry into the nerve terminal Proceedings of the National Academy of Sciences 108(11): 4477-4481. DOI: 10.1073/pnas.1017837108

Photo by Max xx on Flickr; used under a Creative Commons license.

2 comments:

Vinoy Vijayan said...

Looks like an interesting read! Thanks for the write up - going to take a look at the article later today
i do some drosophila neurobio ..so if there is any drosophila stuff that didn't make sense,
i might(?) be able to clarify

Zen said...

Got this from fellow blogger Namnezia, who was having mysterious problems with the comment feed:

"You say: 'Shakiryanova and colleagues claim to have found neurons that release neurotransmitter without calcium being involved at all.'

"I think you might be overstating the case here. That's not what they're saying. They're saying that you don't need extracellular calcium entry to evoke release, but that you can get release using only calcium evoked from internal stores. In fact they say calcium from internal stores is required for their effect. So they are not ruling out calcium at all.

"Finally, just because they can experimentally block extracellular calcium entry and evoke release through this other mechanism, doesn't mean that that's the way that neuron works normally. To quote from their abstract: 'Hence, rather than relying exclusively on activity-dependent Ca2+ entry into the nerve terminal, a behaviorally important neuromodulator uses synergistic cAMP-dependent protein kinase and endoplasmic reticulum Ca2+ signaling to induce synaptic neuropeptide release.' Synergistic being the key word."