3 research outputs found
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
The nicotinic acetylcholine receptor alpha 4 subunit contains a functionally relevant SNP Haplotype
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