The nicotinic acetylcholine receptor alpha 4 subunit contains a functionally relevant SNP Haplotype

Background Non-coding single nucleotide polymorphisms within the nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4) are robustly associated with various neurological and behavioral phenotypes including schizophrenia, cognition and smoking. The most commonly associated polymorphisms are located in exon 5 and segregate as part of a haplotype. So far it is unknown if this haplotype is indeed functional, or if the observed associations are an indirect effect caused by linkage disequilibrium with not yet identified adjacent functional variants. We therefore analyzed the functional relevance of the exon 5 haplotype alleles. Results Using voltage clamp experiments we were able to show that the CHRNA4 haplotype alleles differ with respect to their functional effects on receptor sensitivity including reversal of receptor sensitivity between low and high acetylcholine concentrations. The results indicate that underlying mechanisms might include differences in codon usage bias and changes in mRNA stability. Conclusions Our data demonstrate that the complementary alleles of the CHRNA4 exon 5 haplotype are functionally relevant, and might therefore be causative for the above mentioned associations

Zellautonome, homöostatische Regulation der elektrischen Erregbarkeit von Körperwandmuskelzellen der Taufliege Drosophila melanogaster

It is essential for excitable cells to keep their activity within a physiological and appropriate range independently from changes in synaptic efficacy or cellular excitability which can occur during phases of learning and/or development. Recently shown results indicated that excitable cells like neurons and muscles are capable of regulating their own activity. Most of those studies, however showed compensatory effects at the level of synaptic efficacy. Those showing changes in ion channel expression to maintain cellular excitability are rare and therefore less understood. Using the advantages of the Drosophila Gal4/UAS-System I generated muscle-specific mutant larvae that expressed a modified Shaker-potassium channel leading to a dramatically decreased cellular excitability. The aim of this work was to detect possible compensatory changes at the level of ion channels and study the underlying cellular mechanisms. Measurements of muscle performance did not display severe impairments in the contractile properties (tension and kinetics) when mutants were compared with wildtypes thus suggesting some kind of compensatory changes. Additional experiments excluded changes of motor synaptic transmission and/or motoneuronal output. On the level of ion channels, an increased calcium current amplitude of about 30% was detected in mutant muscle cells, which was accompanied by an up-regulation of the corresponding calcium channel beta-subunit expression rate. Finally a different mutant was tested, which expressed the Shaker gene late in development and thus had only a limited time for possible compensation. In contrast to the "early" shaker-mutant, this "late" mutant showed impaired muscle performance. This experiment suggested that the expression of the genetically modified potassium channel leads to severe impairments of contractile properties if the effect had no time to be compensated by an increased calcium current