TY - JOUR
T1 - Stabilization of acetylcholine receptors at the neuromuscular synapse
T2 - the role of the nerve
AU - Ramsay, David A.
AU - Drachman, Daniel B.
AU - Drachman, Richard J.
AU - Stanley, Elis F.
N1 - Funding Information:
Acknowledgements. This work was supported by U.S. Army Contract DAMD17-85-C-5069 and a grant from the NIH No. 1R01 NS23719. We are grateful to Dr. David Mellits who carried out biostatistical calculations. We thank Robert N. Adams and Po-Jen Shih for technical assistance, and Christine Fackler Salemi for her patience in preparation of the manuscript.
PY - 1992/5/29
Y1 - 1992/5/29
N2 - The majority of acetylcholine receptors (AChRs) at innervated neuromuscular junctions (NMJs) are stable, with half-lives averaging about 11 days in rodent muscles. In addition to the stable AChRs, approximately 18% of AChRs at these innervated junctions are rapidly turned over (RTOs), with half lives of less than 24 h. We have postulated that RTOs may be precursors of stable AChRs, and that the motor nerve may influence their stabilization. This hypothesis was tested by: (i) labeling AChRs in mouse sternomastoid (SM) muscles with 125I-α-BuTx; (ii) denervating one SM muscle in each mouse, and (iii) following the fate of the labeled AChRs through a 5-day period when RTOs were either stabilized or degraded. The hypothesis predicts that denervation should preclude stabilization of RTOs, resulting in a deficit of stable AChRs in denervated muscles. The results showed a highly significant (P < 0.002) deficit of stable AChRs in denervated as compared with innervated muscles. Control experiments excluded the possibility that this deficit could be attributed to independent accelerated degradation of either RTOs or pre-existing stable AChRs. The observed deficit was quantitatively consistent with the deficit predicted by a mathematical model based on interruption of stabilization following denervation. We conclude that: (i) the observed deficit after denervation of NMJs is due to failure of stabilization of pre-existing RTOs; (ii) RTOs at normally innervated NMJs are precursors of stable AChRs; (iii) stabilization occurs after the insertion of AChRs at NMJs, and (iv) motor nerves play a key role in stabilization of RTOs. The concept of receptor stabilization has important implications for understanding the biology of the neuromuscular junction and post-synaptic plasticity.
AB - The majority of acetylcholine receptors (AChRs) at innervated neuromuscular junctions (NMJs) are stable, with half-lives averaging about 11 days in rodent muscles. In addition to the stable AChRs, approximately 18% of AChRs at these innervated junctions are rapidly turned over (RTOs), with half lives of less than 24 h. We have postulated that RTOs may be precursors of stable AChRs, and that the motor nerve may influence their stabilization. This hypothesis was tested by: (i) labeling AChRs in mouse sternomastoid (SM) muscles with 125I-α-BuTx; (ii) denervating one SM muscle in each mouse, and (iii) following the fate of the labeled AChRs through a 5-day period when RTOs were either stabilized or degraded. The hypothesis predicts that denervation should preclude stabilization of RTOs, resulting in a deficit of stable AChRs in denervated muscles. The results showed a highly significant (P < 0.002) deficit of stable AChRs in denervated as compared with innervated muscles. Control experiments excluded the possibility that this deficit could be attributed to independent accelerated degradation of either RTOs or pre-existing stable AChRs. The observed deficit was quantitatively consistent with the deficit predicted by a mathematical model based on interruption of stabilization following denervation. We conclude that: (i) the observed deficit after denervation of NMJs is due to failure of stabilization of pre-existing RTOs; (ii) RTOs at normally innervated NMJs are precursors of stable AChRs; (iii) stabilization occurs after the insertion of AChRs at NMJs, and (iv) motor nerves play a key role in stabilization of RTOs. The concept of receptor stabilization has important implications for understanding the biology of the neuromuscular junction and post-synaptic plasticity.
KW - Acetylcholine receptor
KW - Neuromuscular junction
KW - Plasticity
KW - Receptor kinetics
KW - Receptor stabilization
KW - Receptor turnover
UR - http://www.scopus.com/inward/record.url?scp=0026628843&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0026628843&partnerID=8YFLogxK
U2 - 10.1016/0006-8993(92)90709-I
DO - 10.1016/0006-8993(92)90709-I
M3 - Article
C2 - 1393528
AN - SCOPUS:0026628843
SN - 0006-8993
VL - 581
SP - 198
EP - 207
JO - Brain research
JF - Brain research
IS - 2
ER -