Evidence for a neural inhibitory factor which downregulates fetal-type acetylcholine receptor expression in skeletal...

Nerve-evoked muscle depolarisation plays an important role in the downregulation of extrasynaptic AChRs which accompanies the increase in synaptic AChR expression at the neuromuscular junction during embryonic development. However, additional mechanisms may be involved in the AChR downregulation. This study provides evidence for a neurotrophic factor present in adult and embryonic chick neural extracts which downregulates fetal-type AChR density independently of depolarisation. Treatment of skeletal muscle cell lines with crude neural extracts decreased AChR density up to 50%, as measured by changes in 125I-alpha-bungarotoxin binding levels. Decreases in membrane-bound AChR density were accompanied by a decrease in the size of the intracellular AChR pool; RT-PCR analysis demonstrated that extract treatment also induced a decrease in gamma-subunit mRNA expression. These studies demonstrate that crude neural extracts contain a factor which may account for the activity-independent regulatory mechanism previously proposed to operate in concert with activity-dependent mechanisms to downregulate fetal-type AChR expression.