Metabolic stabilization of acetylcholine receptors at newly formed neuromuscular junctions in rat

Reiness, Gary; Weinberg, Crispin B.

doi:10.1016/0012-1606(81)90392-4

Cited by 74 publications

(33 citation statements)

References 34 publications

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“…It appears, therefore, that even at established adult end-plates receptor density and receptor metabolism are not tightly coupled. This is consistent with previous observations that during development receptor aggregation, receptor function and receptor metabolism appear to be independently controlled (Steinbach et al 1979;Fischbach & Schuetze, 1980;Reiness & Weinberg, 1981;Michler & Sakmann, 1980;Steinbach, 1981a (Burden, Sargent & McMahan, 1979;Bader, 1981). It is possible that molecules in the basal lamina, which are removed or modified by collagenase treatment, also play a role in determining the metabolic stability of junctional ACh receptors; these molecules may be sensitive to enzymes released at end-plates after denervation.…”

Section: Discussionsupporting

confidence: 90%

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

Bevan¹,

Steinbach²

1983

The Journal of Physiology

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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.

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Section: Discussionsupporting

confidence: 90%

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

Bevan¹,

Steinbach²

1983

The Journal of Physiology

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“…In this study of the adult innervated junction, the total receptors both at the thickened pjm and at the bottom folds turn over with a hall-life of >5 d and are within the range of values given for slow junctional receptors (3,6,7,9,18,20,22,30,31,41). Since the turnover of receptors at the bottom folds is slow, this population cannot be equated with postdenervation ¢xtrajunctional type receptors, even though their site density is low.…”

Section: Total Receptorssupporting

confidence: 55%

Distribution and turnover rate of acetylcholine receptors throughout the junction folds at a vertebrate neuromuscular junction.

Salpeter¹,

Harris²

1983

The Journal of Cell Biology

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ABSIRACI The distribution and turnover rate of acetylcholine receptors labeled with t2Sl-~x-bungarotoxin were examined in innervated mouse sternomastoid muscle by electron microscope autoradiography using the "mask" analysis procedure. We compared the total population of receptors with receptors newly inserted at the junction 2 d after inactivation with nonradioactive cz-bungarotoxin, both at the top {thickened) region of the postjunctional folds (pjm) and the nonthickened bottom folds. We found that the receptor site density was -10 times greater on the thickened pjm than on the nonthickened bottom folds for both total and newly inserted receptors. This ratio does not change significantly during a 6-d period after labeling the new receptors. Furthermore, calculated values for turnover time of receptors show that both total and newly inserted receptors at both regions of the junctional folds have half-lives for degradation within the range given in the literature for slow junctional receptors. These data exclude a simple migration model whereby receptors are preferentially inserted in the nonthickened region of the junctional folds and then migrate into the thickened membrane at a rate equal to the turnover-rate of the receptors.The postsynaptic folds of the vertebrate neuromuscular junction are heterogeneous in terms of both receptor distribution and morphology. The top ~2,000 A of postjunctional membrane (pjm) has a distinct electron density, a cytoplasmic filamentous substructure (4) and is rich in intramembrane particles (13,26,28). This thickened region has a high density of receptors (~10,000-20,000 sites/#m 2) (2,15,16, 19,23,27). At the bottom of the folds, the membrane is morphologically indistinguishable from that at extrajunctional regions, and the receptor site density is considerably reduced (~ 1,000 sites//.tm 2, or ~5-10% the site density at the top of the folds). This site density is equivalent to that seen in the perijunctional region, 0.5-1 #m immediately surrounding each axonal end bouton (16).The reason for the heterogeneity in the organization of the pjm has not yet been established. Much is known about the properties of extrajunctional and junctional receptors both during development and after denervation (for review see references 10, 14). However, nothing is known about the properties of the acetylcholine receptor (AChR) at the bottom, nonthickened region of the pjm. In the present study, we asked two questions: (a) Do the AChRs in the nonthickened bottom folds resemble extrajunctional or embryonic receptors in having a fast turnover rate, and (b) do the nonthickened bottom folds provide a region for the insertion of AChRs that subsequently migrate to the thickened pjm7 We used innervated mouse sternomastoid muscle to examine both the localization and turnover rate of junctional receptors at the top thickened pjm and at the bottom nonthickened membrane. We did this for the total population of receptors as well as for receptors newly inserted at the junction during a 2-d period. We found t...

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“…Such end-plates are formed de novo by a foreign motor nerve transplanted onto the extrajunctional membrane of denervated muscle fibres. They develop within 2-3 weeks along a pattern similar to the one at normal end-plates, with a nerve-induced accumulation of ACh receptors at the site of neuromuscular contact (L0mo & Slater, 1980a) followed by their metabolic stabilization (Reiness & Weinberg, 1981), the deposition of acetylcholinesterase (L0mo & Slater, 1980b) and ending with channel conversion and the formation of junctional folds (Brenner & Sakmann, 1983;Korneliussen & Sommerschild, 1976). We found that, in rat muscle, activity does promote the appearance of the adult channel type at maturing end-plates even if neural influences are eliminated by denervation at an early stage of end-plate development.…”

Section: Introductionmentioning

confidence: 97%

Control of end‐plate channel properties by neurotrophic effects and by muscle activity in rat.

Brenner

Lømo

Williamson

1987

The Journal of Physiology

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SUMMARY1. The formation of ectopic neuromuscular synapses was induced in rat soleus muscle by implantation of the fibular nerve into the proximal part of the muscle and subsequent sectioning of the soleus nerve. The gating properties of acetylcholine (ACh) receptors at the newly formed end-plates were examined by analysis of acetylcholine-induced membrane current fluctuations.2. In agreement with earlier studies, the apparent mean open time of end-plate channels decreased during synaptic development from about 4 ms to about 1 ms (-60 mV membrane potential, 22°C) within 7-18 days after the soleus nerve had been cut.3. When the fibular nerve was cut at an early stage of end-plate development, fast-gating channels with apparent mean open times of 1 ms characteristic of mature end-plates did not develop within the next 10-14 days.4. When the fibular nerve was cut at an early stage of end-plate development and the soleus muscle was then stimulated chronically via implanted electrodes, fastgating channels did develop in the absence of the nerve terminals within 4-6 days.5. When impulse conduction in the transplanted fibular nerve was blocked chronically at the time of soleus nerve section such that ectopic end-plates formed in inactive muscle, fast-gating channels developed within 12-14 days.6. The results show that motoneurones control the conversion from slow-gating fetal to fast-gating adult-type ACh receptor channels at ectopic end-plates in rat soleus muscles. The conversion occurs in the absence of impulse activity provided the nerve continues to be present. However, it also occurs in the absence of the nerve provided the muscle is active and had received an early priming influence from the nerve. Thus, nerve-evoked muscle activity and nerve-released trophic influences complement each other in controlling the gating properties ofjunctional ACh receptor channels.

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Metabolic stabilization of acetylcholine receptors at newly formed neuromuscular junctions in rat

Cited by 74 publications

References 34 publications

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

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

Distribution and turnover rate of acetylcholine receptors throughout the junction folds at a vertebrate neuromuscular junction.

Control of end‐plate channel properties by neurotrophic effects and by muscle activity in rat.

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