Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.
When one brain cell passes its message along to the next cerebral neuron down the line, the transaction involves three key players, to wit: (1) vesicles loaded with neurotransmitters, (2) a membrane on the recipient neuron and (3) a gap - the synapse - that the vesicle must vault over to deliver its cargo.
Conceptually, a vesicle first "kissed" the membrane at the nerve terminal, releasing part of its contents, then "ran away" to be quickly recycled.
This not-so-simple mechanism has embroiled one of neuroscience's hottest debates. Until now, researchers had thought that neurotransmitter release occurred in an all-or-nothing fashion. Instead, new evidence suggests that briefer, more flirtatious encounters take place. Solid quantitative data supporting the kiss-and-run fusion at conventional synapses have been virtually lacking - until last week.
The contrary concept emerged in two separate but highly similar articles in the current Nature, dated June 5, 2003. One bears the title "Three modes of synaptic vesicular recycling revealed by single-vesicle imaging." Its authors are neurobiologists at the Salk Institute in La Jolla, Calif. The second paper, a few pages away, is titled "Single synaptic vesicles fusing transiently and successively without loss of identity." It is authored by molecular and cellular physiologists at Stanford University School of Medicine in Stanford, Calif.
Both contending reports are wrapped up in a "News & Views" commentary headed "All change at the synapse," contributed by scientists at the University of Colorado in Denver. They explain: "Synaptic transmission - the transfer of information between nerve cells - is the most important aspect of brain function. When electrical impulses propagate to the end of a neuron, they evoke the release of chemicals called neurotransmitters. These are stored inside the neuron in small membrane-bound vesicles - rather like a soap bubble within a larger soap bubble. They are released en masse through a pore that forms when the vesicle membrane fuses with the neuron's surface membrane."
The Salk and Stanford papers each reports employing different fluorescent markers to track the fate of individual synaptic vesicles, following a single electric shock, in living neurons from the hippocampal region (site of memory and cognition) of rat brains. "Both groups conclude," the commentary continues, "that a large fraction of neurotransmitter-release events involve kiss-and-run, not vesicle collapse."
The Salk group found that vesicles are retrieved in one of three ways. Some vesicles stay open briefly before retrieval and do not collapse fully into the surface membrane (i.e., "kiss-and-run"), which lasts tenths of a second. Others stay open for longer and probably also do not collapse ("compensatory"), which takes seconds. Still others do collapse and are not retrieved until another stimulus is delivered. This third, "stranded," mode requires tens of seconds.
Stanford's experimental evidence, its co-authors conclude, "supports a predominance of kiss-and-run fusion events and rapid vesicular re-use."
Leading But Two-Edged Heart Remedy Teams With Antifungal Agent In Fungus-Killing Duet
The emergence of drug-resistant fungi poses an increasing threat to the treatment of opportunistic fungal infections in patients with compromised immune systems, as occurs commonly in cancer and AIDS. This can be countered only by the discovery of new antifungal agents. One such compound is far from new.
Scientists at the Johns Hopkins University School of Medicine have determined why amiodarone (AMD), a drug routinely used to treat cardiac arrhythmias, might become a crucial addition to fighting chronic fungal infections. Their paper, released online June 5, 2003, in the Journal of Biological Chemistry, is titled "Antifungal activity of amiodarone is mediated by disruption of calcium homeostasis."
AMD is approved by FDA to treat life-threatening and severe disturbances in the heart's natural rhythm. At higher doses, or given for a long time, AMD's side effects can include severe toxicity to the lungs and thyroid. In the current study, authors tested AMD on a collection of yeast mutants, each one missing a different gene. While yeast isn't life-threatening, some fungi can be pretty nasty in people with depressed immune systems. In laboratory experiments, low doses of AMD were combined with fluconazole, a leading antifungal. The combination proved "strikingly synergistic," and killed about 95 percent of two pathogenic fungi - Candida albicans and Cryptococcus neoformans. This cocktail, the authors point out, has not yet been submitted to the FDA for approval.
Oddball Insect Variety, Strepsiptera, Holes Up Inside Skin Of Target Host Insects; Here's How
Members of a bizarre parasitic insect order known as Strepsiptera avoid detection by ensconcing inside a piece of their host's skin. Strepsipterans reside in a variety of insect species, such as ants, cockroaches, crickets, grasshoppers and bees. Usually, host immune systems recognize these endoparasites and reject the invader. However, entomologists have been unable to identify Strepsiptera's mechanism for rejecting rejection - especially in such a large spectrum of target hosts.
To learn more about the life history of this offbeat bug - which numbers some 400 species and counting - entomologists at the University of Oxford in the UK observed samples of the predatory insect before, during and after host invasion. They report their findings in the Proceedings of the National Academy of Sciences (PNAS) online, dated June 3, 2003. Their paper is titled "Masquerading as self? Endoparasitic Strepsiptera (insects) enclose themselves in host-derived epidermal bag.'"
The scientists saw that after Strepsiptera approached a potential host, it jabbed its head repeatedly into the target bug's cuticle. After about a day of constant drilling motion, a hole formed in the cuticle, which then separated from the host's epidermis. By continuing to jab and writhe, the invading insect forced itself into the epidermis, which enclosed the parasite like a bag. Observing the enclosed intruders in a liquid medium showed that Strepsiptera grew, molted and absorbed all its nutrients through the sac. The authors suggest that because the bag prevents immune detection, Strepsiptera has the ability to inhibit many diverse host species.