Voltage-dependent calcium channels play a role in many cellular phenomena. Very little is known about Ca2+ channels in Drosophila, especially those in muscles. Existing literature on neuronal Ca2+ channels of Drosophila suggests that their pharmacology may be distinct from that of vertebrate Ca2+ channels. This raises questions on the pharmacology and diversity of Ca2+ channels in Drosophila muscles. Here we show that the Ca2+ channel current in the body-wall muscles of Drosophila larvae consists of two main components. One component is sensitive to 1,4-dihydropyridines and diltiazem, which block vertebrate L-type Ca2+ channels. The second component is sensitive to amiloride, which blocks vertebrate T-type Ca2+ channels. In contrast to Drosophila brain membrane preparations in which a majority of the Ca2+ channels are phenylalkylamine-sensitive but dihydropyridine-insensitive, the major current in the muscles was dihydropyridine-sensitive but relatively less sensitive to verapamil. This might indicate an underlying tissue specific distribution of distinct subtypes of dihydropyridine/phenylalkylamine-sensitive Ca2+ channels in Drosophila. Low verapamil sensitivity of the dihydropyridine-sensitive current of Drosophila muscles also set it apart from the vertebrate L-type channels which are sensitive to 1,4-dihydropyridines, benzothiazepines as well as phenylalkylamines. The dihydropyridine-sensitive current in Drosophila muscles activated in a similar voltage range as the vertebrate L-type current. As with the vertebrate current, blockade by dihydropyridines was voltage dependent.(ABSTRACT TRUNCATED AT 250 WORDS)
Mitochondrial dysfunction is a significant factor in human disease, ranging from systemic disorders of childhood to cardiomyopathy, ischaemia and neurodegeneration. Cytochrome oxidase, the terminal enzyme of the mitochondrial respiratory chain, is a frequent target. Lower eukaryotes possess alternative respiratory-chain enzymes that provide non-proton-translocating bypasses for respiratory complexes I (single-subunit reduced nicotinamide adenine dinucleotide dehydrogenases, e.g. Ndi1 from yeast) or III + IV [alternative oxidase (AOX)], under conditions of respiratory stress or overload. In previous studies, it was shown that transfer of yeast Ndi1 or Ciona intestinalis AOX to Drosophila was able to overcome the lethality produced by toxins or partial knockdown of complex I or IV. Here, we show that AOX can provide a complete or substantial rescue of a range of phenotypes induced by global or tissue-specific knockdown of different cIV subunits, including integral subunits required for catalysis, as well as peripheral subunits required for multimerization and assembly. AOX was also able to overcome the pupal lethality produced by muscle-specific knockdown of subunit CoVb, although the rescued flies were short lived and had a motility defect. cIV knockdown in neurons was not lethal during development but produced a rapidly progressing locomotor and seizure-sensitivity phenotype, which was substantially alleviated by AOX. Expression of Ndi1 exacerbated the neuronal phenotype produced by cIV knockdown. Ndi1 expressed in place of essential cI subunits produced a distinct residual phenotype of delayed development, bang sensitivity and male sterility. These findings confirm the potential utility of alternative respiratory chain enzymes as tools to combat mitochondrial disease, while indicating important limitations thereof.
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