The high sensitivity of voltage-gated ion channels to changes in membrane potential implies that the process of channel opening is accompanied by large charge movements. Previous estimates of the total charge displacement, q, have been deduced from the voltage dependence of channel activation and have ranged from 4 to 8 elementary charges (e0). A more direct measurement of q in Drosophila melanogaster Shaker 29-4 potassium channels yields a q value of 12.3 e0. A similar q value is obtained from mutated Shaker channels having reduced voltage sensitivity. These results can be explained by a model for channel activation in which the equilibria of voltage-dependent steps are altered in the mutant channels.

Olfaction is of considerable importance to many insects in behaviors critical for survival and reproduction, including location of food sources, selection of mates, recognition of colony con-specifics, and determination of oviposition sites. An ubiquitous, but poorly understood, component of the insect's olfactory system is a group of odorant-binding proteins (OBPs) that are present at high concentrations in the aqueous lymph surrounding the dendrites of olfactory receptor neurons. OBPs are believed to shuttle odorants from the environment to the underlying odorant receptors, for which they could potentially serve as odorant presenters. Here we show that the Drosophila genome carries 51 potential OBP genes, a number comparable to that of its odorant-receptor genes. We find that the majority (73%) of these OBP-like genes occur in clusters of as many as nine genes, in contrast to what has been observed for the Drosophila odorant-receptor genes. Two of the presumptive OBP gene clusters each carries an odorant-receptor gene. We also report an intriguing subfamily of 12 putative OBPs that share a unique C-terminal structure with three conserved cysteines and a conserved proline. Members of this subfamily have not previously been described for any insect. We have performed phylogenetic analyses of the OBP-related proteins in Drosophila as well as other insects, and we discuss the duplication and divergence of the genes for this large family.

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We report the identification of bang senseless (bss), a Drosophila melanogaster mutant exhibiting seizure-like behaviors, as an allele of the paralytic (para) voltage-gated Na 1 (Na V ) channel gene. Mutants are more prone to seizure episodes than normal flies because of a lowered seizure threshold. The bss phenotypes are due to a missense mutation in a segment previously implicated in inactivation, termed the ''paddle motif'' of the Na V fourth homology domain. Heterologous expression of cDNAs containing the bss 1 lesion, followed by electrophysiology, shows that mutant channels display altered voltage dependence of inactivation compared to wild type. The phenotypes of bss are the most severe of the bang-sensitive mutants in Drosophila and can be ameliorated, but not suppressed, by treatment with anti-epileptic drugs. As such, bss-associated seizures resemble those of pharmacologically resistant epilepsies caused by mutation of the human Na V SCN1A, such as severe myoclonic epilepsy in infants or intractable childhood epilepsy with generalized tonic-clonic seizures.

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In a given population, certain individuals are much more likely to have seizures than others. This increase in seizure susceptibility can lead to spontaneous seizures, such as seen in idiopathic epilepsy, or to symptomatic seizures that occur after insults to the nervous system. Despite the frequency of these seizure disorders in the human population, the genetic and physiological basis for these defects remains unclear. The present study makes use of Drosophila as a potentially powerful model for understanding seizure susceptibility in humans. In addition to the genetic and molecular advantages of using Drosophila, it has been found that seizures in Drosophila share much in common with seizures seen in humans. However, the most powerful aspect of this model lies in the ability to accurately measure seizure susceptibility across genotypes and over time. In the current study seizure susceptibility was quantified in a variety of mutant and wild-type strains, and it was found that genetic mutations can modulate susceptibility over an extremely wide range. This genetic modulation of seizure susceptibility apparently occurs without affecting the threshold of individual neurons. Seizure susceptibility also varied depending on the experience of the fly, decreasing immediately after a seizure and then gradually increasing over time. A novel phenomenon was also identified in which seizures are suppressed after certain high-intensity stimuli. These results demonstrate the utility of Drosophila as a model system for studying human seizure disorders and provide insights into the possible mechanisms by which seizure susceptibility is modified.