Denervation increases the degradation rate of acetylcholine receptors at end‐plates in vivo and in vitro.

Abstract

SUMMARY1. We have studied the effect of denervation on the degradation of the existing junctional acetylcholine (ACh) receptors at end-plates in rat muscles. ACh receptors were labelled by injecting animals with iodinated a-bungarotoxin (I-aBT); 1 day later the left hemidiaphragm was denervated. The degradation of bound I-aBT in normal and denervated muscles was examined in organ culture, beginning at various times after denervation in vivo.2. The original, pre-labelled end-plate ACh receptors are degraded more rapidly after denervation. The rate of degradation begins to increase shortly after the nerve is cut and reaches a maximum value at about 9 days of denervation.3. Muscles denerva~ted only on transfer to organ culture also show an increase in the degradation rate of bound I-aBT with increasing time of denervation (time in culture).4. In normal diaphragm muscles, the initial rate of degradation of functional ACh receptors, after correcting for non-degradative loss of I-aBT, is 010018 h-1 (tj = 383 h). The maximal rate at denervated end-plates is 010073 h-1 (tj = 94 h). For soleus, sternomastoid, plantaris and intercostal innervated muscles the apparent rate of ACh receptor degradation either in vitro or in vivo ranged from 010005 h-1 to 0-002 h-1. 5. The rate of loss of bound I-aBT in vivo is more rapid at denervated end-plates than at innervated end-plates. For diaphragm muscles, the rates ofI-acBT degradation measured in organ culture are able to describe the relative rates of loss of I-aBT from innervated and denervated muscles in vivo.6. At short times after labelling, a fraction (10-20%) of the I-BT bound to innervated muscles is degraded more rapidly than the remaining toxin. The possibility that these I-BT binding sites are degraded at the rate characteristic of extrajunctional receptors on denervated muscle fibres is discussed.

Acetylcholine Receptors in Innervated Muscles of DystrophicmdxMice Degrade as after Denervation

“…2). Furthermore, although the Rs in the control soleus muscles accelerated with a ϳ5 d delay after denervation, as described previously for these muscles (Bevan and Steinbach, 1983;Andreose et al, 1993), the Rs on mdx muscles did not accelerate f urther after denervation but maintained their already accelerated predenervation degradation values.…”

On the effect of muscle activity on the end‐plate membrane in denervated mouse muscle.

“…This may arise from the statistical error inherent in counting low amounts of radioactivity in small bundles of muscle fibres and estimating low turnover rates from data collected over short culturing periods. In denervated-active muscles, additional discrepancy would arise if they, unlike innervated muscles (Bevan & Steinbach, 1983), did not contain a small population of low-stability AChRs in their end-plates. The metabolic stabilization of AChRs by muscle activity may be important for the maintenance of a sufficient number of junctional AChRs to support neuromuscular transmission.…”

Developmental changes in the half‐life of acetylcholine receptors in the myotomal muscle of Xenopus laevis.

“…In some experiments the radioactivity in the culture medium was analysed on a Biorad P-2 chromatographic column in order to assess how much resulted from degradation and how much from unbinding of '25IaBT (Bevan & Steinbach, 1983). By knowing how much l25IaBT appeared in the culture medium during a given period of time, and the initial amount of bound L25LxBT, the rate constant of unbinding could be readily calculated.…”