Neural regulation of mRNA for the alpha-subunit of acetylcholine receptors: role of neuromuscular transmission

Abstract

Levels of mRNA for acetylcholine receptor (AChR) subunits are relatively low in innervated skeletal muscles. Following denervation they rise rapidly, leading to increased AChR synthesis. The mechanism by which motor nerves normally regulate these mRNA levels is not yet known. In order to determine the possible role of synaptic transmission in this process, we have compared the effect of blockade of cholinergic ACh transmission with that of surgical denervation. Blockade of quantal ACh transmission was produced by injection of type A botulinum toxin into the soleus muscles of rats. We measured mRNA for the alpha-subunit of the AChR (alpha-AChR mRNA) in RNA extracts of botulinum-treated, denervated, and normal control muscles by hybridization with a highly specific cDNA probe. Our findings show that treatment with botulinum toxin resulted in an increase in alpha-AChR mRNA which was similar to the effect of surgical denervation, although slower in its time course. Since botulinum toxin specifically inhibits quantal ACh release, these results support the concept that cholinergic synaptic transmission plays a key role in mediating the neural control of the alpha-AChR message. The difference between the effects of denervation and botulinum-treatment may be explained by the fact that botulinum toxin does not block the spontaneous non-quantal component of ACh transmission, which has previously been shown to have a partial influence in regulating certain properties of muscles. The present results suggest that synaptic transmission has an important influence in regulating gene expression in the target cell.